Abstract

From the time of first characterization of PI3K as a heterodimer made up of a p110 catalytic subunit and a regulatory subunit, a wealth of evidence have placed the class IA PI3Ks at the forefront of drug development for the treatment of various diseases including cancer. The p110α isoform was quickly brought at the centre of attention in the field of cancer research by the discovery of cancer-specific gain-of-function mutations in PIK3CA gene in a range of human solid tumours. In contrast, p110δ PI3K was placed into the spotlight of immunity, inflammation and haematologic malignancies because of the preferential expression of this isoform in leucocytes and the rare mutations in PIK3CD gene. The last decade, however, several studies have provided evidence showing that the correlation between the PIK3CA mutations and the response to PI3K inhibition is less clear than originally considered, whereas concurrently an unexpected role of p110δ PI3K in solid tumours has being emerging. While PIK3CD is mostly non-mutated in cancer, the expression levels of p110δ protein seem to act as an intrinsic cancer-causing driver in various solid tumours including breast, prostate, colorectal and liver cancer, Merkel-Cell carcinoma, glioblastoma and neurobalstoma. Furthermore, p110δ selective inhibitors are being studied as potential single agent treatments or as combination partners in attempt to improve cancer immunotherapy, with both strategies to shown great promise for the treatment of several solid tumours. In this review, we discuss the evidence implicating the p110δ PI3K in human solid tumours, their impact on the current state of the field and the potential of using p110δ-selective inhibitors as monotherapy or combined therapy in different cancer contexts.

History of PI3Ks at a glance

It has been 35 years since researchers found the humble beginning of PI3Ks via the first report showing that there is a dynamic association between a phosphatidylinositol kinase activity and various viral oncoproteins [1–3]. A couple of years later, this oncoprotein-associated lipid kinase was found to catalyze the phosphorylation of phosphatidylinositol on the 3-OH position of the inositol ring producing a new phosphoinositide [4], the PI(3,4,5)P3 (phosphatidylinositol(3,4,5)trisphosphate; PIP3), which later on was found in GPCRs-stimulated neutrophils [5,6] and in cells stimulated by tyrosine kinase agonists [7–10]. Concurrently, several research groups had discovered that PI3K is a heterodimer made up of a p110 catalytic subunit and a regulatory subunit [11–21]. It was in 1992 when the cDNA of p110α catalytic subunit of PI3K was isolated [22] and this was followed by the discovery of the other PI3K isoforms in various species [23–36]. PI3Ks were then divided into three classes, class I, class II and class III [37,38]. Class I is subdivided in class IA which consists of p110α, p110β and p110δ and class IB consisting of p110γ. Class II includes the PI3K-C2a, PI3K-C2b, PI3K-Cg and class III the vps34p [39].

The next goal of PI3K research was to identify whether PI3Ks have isoform specific functions. The first evidence came for class I PI3Ks showing that these enzymes have identical enzymatic activities but they have non-redundant functions [40–49]. Concurrent with these data, the tissue distribution of class I PI3K was also revealed showing that p110α and p110β are globally expressed [27,50–52], whereas p110γ and p110δ are predominantly expressed in white blood cells [25,32]. New evidence however revealed that p110δ is also expressed at high levels in some cancer cell lines and human tissues of non-leucocyte origin such as breast cancer cells [53,54] and at moderate levels in neurons [55].

An important discovery for the PI3K field was the identification of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) lipid phosphatase [56]. The PTEN tumour suppressor was found to be a PI(3,4,5)P3 phosphatase which antagonizes the PI3K activity [56] controlling thus cell survival [57–59] whereas reduced or lost activity of PTEN contributes to constitutive activation of the PI3K pathway [60–63] and to abnormal cell growth [64–66]. Relatively later after the discovery of PTEN, a big step forward was made by the identification of cancer-specific gain-of-function mutations in PIK3CA gene [67,68], which encodes the p110α PI3K. Since then, the PTEN protein and the p110α PI3K have been considered as promising targets in cancer treatment research. Pharmacological studies have implicated p110β in platelet biology and thrombosis [69] and in tumour cells lacking PTEN [70–74]. The PIK3CD gene encoding the p110δ PI3K is rarely mutated in cancers [67,75–82]. A rare disease called APDS or PASLI [79–81] has been recently correlated with a mutation in PIK3CD gene and a very low frequency mutation in PIK3CD was also found in diffuse large B-cell lymphoma [82]. Because p110δ was originally found to be predominantly expressed in white blood cells [25,32], the interest of the p110δ-focused research was shifted towards the immune system and the role of p110δ PI3K was extensively investigated in immunity, inflammation and in lymphoid and myeloid malignancies [47–49,83–91]. p110δ-selective inhibitors have been studied in multiple haematologic malignancies [88,89] whereas the use of Idelalisib, a potent p110δ-selective inhibitor, was an advancement in the treatment of haematologic malignancies [92].

High expectations for p110α PI3K as an effective target in solid tumours ended up not satisfactory

The discovery of cancer-specific gain-of-function mutations in PIK3CA gene [67,68] and the loss of function mutations in PTEN [56] marked the beginning of an extensive research on p110α PI3K and PTEN as promising targets for the treatment of solid tumours. Especially for breast cancer, the deregulated PI3K signalling has often been attributed to mutations in PIK3CA and/or PTEN gene [64,67,68,93,94] coming to the conclusion that the PIK3CA/PTEN mutational status could be used as a molecular parameter which would predict the sensitivity of cancer cells to PI3K inhibitors.

However, besides the great attention that p110α PI3K and PTEN have received for their involvement in human cancers new evidence showed that the key role which has been credited to PIK3CA/PTEN mutational status may have been overestimated. Indeed, these studies have shown that there is no always significant correlation between the PIK3CA or PTEN mutational status in cancer cell lines and the inhibition of cell growth by PI3K inhibitors [95–97]. Notably, breast cancer cells were found to be sensitive to growth inhibition by class I PI3K inhibitors without having mutations in PTEN or PIK3CA genes [96]. Besides, breast cancer cells with PTEN deficiency were found to be resistant to PI3K inhibitors [97]. Furthermore, an unexplained observation is that although PTEN somatic mutations are not very often in human breast cancers [98], the deregulated PI3K activity in breast cancer cells is not controlled by wild-type PTEN.

All these data together pointed to the conclusion that the basis of PIK3CA/PTEN mutational status for the response of cancer cells to PI3K inhibitors and for patient selection may not be as straightforward as originally hoped for and that alternative mechanisms and/or isoform(s) other than p110α could regulate the PI3K pathway in cancer cells.

p110δ PI3K is being emerging as an effective target in solid tumours

p110δ PI3K and its signalling mechanism play a fundamental role in breast cancer

From the time of cloning and characterization of p110δ PI3K [25,32], this isoform has been considered as a target in immune-related disorders. It was the preferential expression of p110δ in leucocytes [25,32] together with the absence of somatic mutations in PIK3CD gene [67,75–78] that brought p110δ into the spotlight of immune system and haematologic cancers [85–87,89,99]. Research using mice with inactivated p110δ [47–49,83,84] and p110δ-selective inhibitors such as the IC87114, the first isoform-selective inhibitor published [100] and the CAL101 (Idelalisib) shed light on p110δ-isoform specific functions in haematopoietic cells [88,89,101].

Looking back, p110δ PI3K was cloned [25,32] a decade after the first characterization of PI3K as a heterodimer [11,12]. It was not until 2007, however, that the p110δ PI3K-triggered signalling pathway was reported [102]. This is a complex feedback mechanism in which p110δ negatively controls the activity of RhoA GTPase and PTEN tumour suppressor (Figure 1). The activation of p110δ PI3K was found to positively regulate the p190RhoGAP activity and to result in the accumulation of p27 in the cytoplasm [102]. Given that p190RhoGAP catalyses the return of RhoA-GTP (active state) to RhoA-GDP (inactive state) [103] and p27 prevents the return of RhoA-GDP to RhoA-GTP [104], the activation of p110δ leads to decreased RhoA activity and consequently to decreased PTEN activity [102,105]. Upon p110δ inactivation, PTEN becomes activated and dampens the PI3K pathway by impinging on the PI(3,4,5)P3 produced by the remaining active class I PI3K isoforms (Figure 1). Interestingly, this mechanism implies that activation of p110δ PI3K by extracellular stimuli leads to inactivation of wild-type PTEN which could explain the paradox that although PTEN somatic mutations are rare in human breast cancers [98,106], the deregulated PI3K activity in breast cancer cells is not controlled by wild-type PTEN.

p110δ PI3K-triggered signalling pathway

Figure 1
p110δ PI3K-triggered signalling pathway

Activation of p110δ by extracellular stimuli leads to increased activity of p190RhoGAP (through PYK2/Src activation) and to cytoplasmic accumulation of p27 (which is mediated by the increased Akt activity). p190RhoGAP induces the inactivation of RhoA whereas p27 prevents the activation of RhoA both thus leading to reduced RhoA activity and consequently to decreased PTEN activity. Inactivation of p110δ by IC87114 reverses these pathways leading to PTEN activation which then opposes the PI3K reaction of the remaining active p110 isoforms. Arrows represent alterations in activity or location in the presence (red) or in the absence (black) of IC87114.

Figure 1
p110δ PI3K-triggered signalling pathway

Activation of p110δ by extracellular stimuli leads to increased activity of p190RhoGAP (through PYK2/Src activation) and to cytoplasmic accumulation of p27 (which is mediated by the increased Akt activity). p190RhoGAP induces the inactivation of RhoA whereas p27 prevents the activation of RhoA both thus leading to reduced RhoA activity and consequently to decreased PTEN activity. Inactivation of p110δ by IC87114 reverses these pathways leading to PTEN activation which then opposes the PI3K reaction of the remaining active p110 isoforms. Arrows represent alterations in activity or location in the presence (red) or in the absence (black) of IC87114.

The p110δ PI3K signalling pathway was originally found in primary [102] and transformed macrophages [107] and in mouse brain tissue [55]. Further work uncovered that the p110δ protein is expressed at different levels in different cancer contexts, e.g. the p110δ PI3K is the predominant isoform expressed in human primary breast carcinoma and breast cancer cell lines, whereas ovarian and cervical human carcinomas mainly express p110α and p110β PI3K [54] (Table 1). Interestingly, the negative regulation of PTEN by p110δ was found in those cancer contexts where p110δ is expressed at high levels [54]. Moreover, the expression levels of p110δ was found to inversely correlate with PTEN activity in breast cancer cells with the cells expressing the higher p110δ levels having the lower PTEN activity suggesting that the elevated expression of p110δ might provide these cells with a competitive advantage to keep their wild-type PTEN inactive [54]. Consequently, breast cancer cells expressing functional PTEN were found to be sensitive to anti-proliferative effect of p110δ inhibitors through PTEN activation while inhibition of p110δ in ovarian and cervical cancer cells had no effect neither in PTEN activity nor in cell proliferation [54] (Table 1). These data are in line with both the poor correlation between the PIK3CA/PTEN mutational status and the response of breast cancer cells to the anti-proliferative effect of PI3K inhibitors [95–97], and with the good correlation between the PIK3CA gain-of-function mutations and PTEN deficiency and the response of ovarian cancer cells to PI3K pathway inhibitors [97,108–112] that were previously described.

Table 1
p110δ PI3K expression levels correlate with cancer progression in various solid tumour contexts
Solid tumourp110δ PI3K expression/functionEffect of p110δ inhibition/inactivationReference
In vitroIn vivo/patient samplesIn vitroIn vivo
Breast p110δ PI3K is predominantly expressed in breast cancer cell lines.
The p110δ expression levels inversely correlate with PTEN activity.
Elevated p110δ expression levels dampen the activity of PTEN tumor suppressor. 
p110δ PI3K is
predominantly expressed in human breast carcinomas.
p110δ expression increases during breast cancer progression from grade I to III. 
Increased PTEN activity, inhibition of pAkt,
inhibition of cell proliferation 
Abrogation of tumour growth Goulielmaki et al., 2018;
Tzenaki et al., 2012 
Prostate The p110δ expression levels inversely correlate with PTEN activity.
Elevated p110δ expression levels dampen the activity of PTEN tumor suppressor.
Overexpression of p110δ mRNA. 
– Increased PTEN activity,
inhibition of pAkt,
inhibition of cell proliferation 
 Tzenaki et al., 2012;
Jiang et al., 2010 
Colorectal cancer High expression levels of p110δ p110δ overexpression correlates with advanced tumour
stage and distant metastasis protein. 
Suppression of CRC cell growth, migration and invasion
Suppression of cell survival and induction of apoptosis 
Suppression of tumour growth
Abrogation of tumour growth 
Chen et al., 2019;
Yang et al., 2017 
Liver Increased p110δ expression in a chemical carcinogenesis model Increased p110δ expression in HCC patients correlates with poor overall survival Inhibition of cell viability in HCC cell lines and cells derived from patients
Induction of apoptosis 
Abrogation of tumour growth Ko et al., 2018;
Yue and Sun 2018 
Merkel cell carcinoma – High expression levels of p110δ – Complete clinical response to Idelalisib of a patient with stage IV Merkel-cell carcinoma Shiver et al., 2015 
Glioblastoma Overexpression of p110δ mRNA, increased copy number of PIK3CD
Resistance to erlotinib is associated with increased p110δ expression 
– Decreased viability of EGFR-amplified BS153 cells and restoration of erlotinib sensitivity – Knobbe and Reifenberge, 2003;
Mizoguchietal, 2004;
Schulte et al., 2013 
Neuroblastoma Overexpression of p110δ protein Overexpression of p110δ protein Suppression of p110δ expression impaired cell growth and survival – Boller et al., 2008 
Ovarian Very low expression Very low expression No effect – Tzenaki et al., 2012 
Cervical Very low expression Very low expression No effect – Tzenaki et al., 2012 
Solid tumourp110δ PI3K expression/functionEffect of p110δ inhibition/inactivationReference
In vitroIn vivo/patient samplesIn vitroIn vivo
Breast p110δ PI3K is predominantly expressed in breast cancer cell lines.
The p110δ expression levels inversely correlate with PTEN activity.
Elevated p110δ expression levels dampen the activity of PTEN tumor suppressor. 
p110δ PI3K is
predominantly expressed in human breast carcinomas.
p110δ expression increases during breast cancer progression from grade I to III. 
Increased PTEN activity, inhibition of pAkt,
inhibition of cell proliferation 
Abrogation of tumour growth Goulielmaki et al., 2018;
Tzenaki et al., 2012 
Prostate The p110δ expression levels inversely correlate with PTEN activity.
Elevated p110δ expression levels dampen the activity of PTEN tumor suppressor.
Overexpression of p110δ mRNA. 
– Increased PTEN activity,
inhibition of pAkt,
inhibition of cell proliferation 
 Tzenaki et al., 2012;
Jiang et al., 2010 
Colorectal cancer High expression levels of p110δ p110δ overexpression correlates with advanced tumour
stage and distant metastasis protein. 
Suppression of CRC cell growth, migration and invasion
Suppression of cell survival and induction of apoptosis 
Suppression of tumour growth
Abrogation of tumour growth 
Chen et al., 2019;
Yang et al., 2017 
Liver Increased p110δ expression in a chemical carcinogenesis model Increased p110δ expression in HCC patients correlates with poor overall survival Inhibition of cell viability in HCC cell lines and cells derived from patients
Induction of apoptosis 
Abrogation of tumour growth Ko et al., 2018;
Yue and Sun 2018 
Merkel cell carcinoma – High expression levels of p110δ – Complete clinical response to Idelalisib of a patient with stage IV Merkel-cell carcinoma Shiver et al., 2015 
Glioblastoma Overexpression of p110δ mRNA, increased copy number of PIK3CD
Resistance to erlotinib is associated with increased p110δ expression 
– Decreased viability of EGFR-amplified BS153 cells and restoration of erlotinib sensitivity – Knobbe and Reifenberge, 2003;
Mizoguchietal, 2004;
Schulte et al., 2013 
Neuroblastoma Overexpression of p110δ protein Overexpression of p110δ protein Suppression of p110δ expression impaired cell growth and survival – Boller et al., 2008 
Ovarian Very low expression Very low expression No effect – Tzenaki et al., 2012 
Cervical Very low expression Very low expression No effect – Tzenaki et al., 2012 

The in vitro studies on the role of p110δ PI3K in breast cancer was followed by new evidence showing that inhibition of p110δ in vivo has a major impact on breast tumour progression [113]. p110δ-selective inhibitors were found to abrogate breast tumour growth and to prevent metastasis in mice as a result of their great efficacy to inhibit the survival and proliferation of cancer cells [113,114] and moreover to prevent the recruitment of macrophage into tumour sites [113] (and Papakonstanti et al., unpublished data) (Table 1 and Figure 2). Experiments with specific combinations of host animals and grafted tumours revealed an indispensable role of p110δ inactivation in both macrophages and cancer cells for breast tumour growth blockade [113]. p110δ inactivation has been also shown to decrease breast tumour growth by reducing the immune-suppressive function of regulatory T cells (Tregs) in a different model [115]. Given that the inactivation of p110δ blocked breast tumour growth of p110δ-expressing tumours even in the absence of T cells [113], it is possible that the effect of p110δ inhibition on the abundance of TAMs (tumour-associated macrophages) leads to tumour regression through various macrophage-induced mechanisms, one of which might be the CCL22-mediated recruitment of Treg cells [116] (Figure 2). It is noteworthy, however, that the targeted inactivation of p110δ in macrophages was proved to be sufficient to suppress tumour growth and metastasis [113] emerging a substantial impact of p110δ inhibition on tumour stroma in breast cancer. Given that p110δ selective inhibitors have shown remarkable clinical activity as single-agent treatment in CLL by targeting the tumour stroma [117], these data open up new directions for the use of p110δ inhibitors not only in breast cancer but also in other cancer types.

p110δ PI3K inhibition in the interplay among cells of the TME and tumour cells

Figure 2
p110δ PI3K inhibition in the interplay among cells of the TME and tumour cells

Tumour-specific cytolytic CD8+ T cells infiltrate the tumour stroma where potentially recognize and eliminate cancer cells. CTLs anti-tumour response is suppressed through their interaction with other cells of the TME or through immune checkpoint molecules allowing cancer cells to survive and grow. Tumour-associated macrophages (TAMs) secret IL-6 and TNF-α which promote the survival of cancer cells and EGF which attracts neoplastic cells to invade towards TAMs. EGF expression by TAMs is driven through CSF-1R via neoplastic cell production of CSF-1. TAMs can suppress CTL response by releasing IL-10 and TGF-β or through CTLs metabolic starvation which is mediated by indoleamine 2,3- dioxygenase (IDO) and arginase (ARG) or through recruitment of IL-10- and TGF-β-expressing regulatory T cells (Tregs) via CCL22. IL-10 secreted by TAMs and Tregs stimulates the expression of PD-L1 on dendritic cells (DCs) and suppresses the capacity of DCs to produce IL-12 and promote a Th1/CTL anti-tumor immune response. Myeloid-derived suppressor cells (MDSCs) secrete ARG, nitric oxide (NO) and reactive oxygen species (ROS) to block the activity of CTLs and secrete anti-inflammatory cytokines to induce the activity of Tregs. PD-L1 and/or B7-H4 ligands expressed on tumour cells, TAMs, DCs and MDSCs bind to PD-1 or CTLA-4 expressed on CTLs and further promote the inhibitory signals, suppress CTLs activity and lead to CTLs anergy. CTLA-4 also enhances the activity of Tregs leading to immunosuppressive activity. Therapies with antibodies against PD-1 or CTLA-4 are intended to restore CTL anti-tumour activity. Therapeutic efficacy of checkpoint inhibitors can be improved by p110δ PI3K targeting through different ways. p110δ inactivation abrogates tumour cells growth in some cancer contexts, prevents the recruitment of macrophage to tumour sites and indirectly prevents the recruitment of Tregs, inhibits Tregs and MDSCs and activates DCs. The effect of p110δ inhibition on TAMs may further enhance the effectiveness of immune checkpoint inhibitors (ICIs) by indirectly preventing the engagement of B7 ligands expressed in TAMs with PD-1 or CTLA-4 on CTLs which limits CTLs response in the TME (dashed line). p110δ PI3K inhibitors as monotherapy or in a combinatorial regimen with ICIs can more potently stimulate a CTL-anti-tumour response.

Figure 2
p110δ PI3K inhibition in the interplay among cells of the TME and tumour cells

Tumour-specific cytolytic CD8+ T cells infiltrate the tumour stroma where potentially recognize and eliminate cancer cells. CTLs anti-tumour response is suppressed through their interaction with other cells of the TME or through immune checkpoint molecules allowing cancer cells to survive and grow. Tumour-associated macrophages (TAMs) secret IL-6 and TNF-α which promote the survival of cancer cells and EGF which attracts neoplastic cells to invade towards TAMs. EGF expression by TAMs is driven through CSF-1R via neoplastic cell production of CSF-1. TAMs can suppress CTL response by releasing IL-10 and TGF-β or through CTLs metabolic starvation which is mediated by indoleamine 2,3- dioxygenase (IDO) and arginase (ARG) or through recruitment of IL-10- and TGF-β-expressing regulatory T cells (Tregs) via CCL22. IL-10 secreted by TAMs and Tregs stimulates the expression of PD-L1 on dendritic cells (DCs) and suppresses the capacity of DCs to produce IL-12 and promote a Th1/CTL anti-tumor immune response. Myeloid-derived suppressor cells (MDSCs) secrete ARG, nitric oxide (NO) and reactive oxygen species (ROS) to block the activity of CTLs and secrete anti-inflammatory cytokines to induce the activity of Tregs. PD-L1 and/or B7-H4 ligands expressed on tumour cells, TAMs, DCs and MDSCs bind to PD-1 or CTLA-4 expressed on CTLs and further promote the inhibitory signals, suppress CTLs activity and lead to CTLs anergy. CTLA-4 also enhances the activity of Tregs leading to immunosuppressive activity. Therapies with antibodies against PD-1 or CTLA-4 are intended to restore CTL anti-tumour activity. Therapeutic efficacy of checkpoint inhibitors can be improved by p110δ PI3K targeting through different ways. p110δ inactivation abrogates tumour cells growth in some cancer contexts, prevents the recruitment of macrophage to tumour sites and indirectly prevents the recruitment of Tregs, inhibits Tregs and MDSCs and activates DCs. The effect of p110δ inhibition on TAMs may further enhance the effectiveness of immune checkpoint inhibitors (ICIs) by indirectly preventing the engagement of B7 ligands expressed in TAMs with PD-1 or CTLA-4 on CTLs which limits CTLs response in the TME (dashed line). p110δ PI3K inhibitors as monotherapy or in a combinatorial regimen with ICIs can more potently stimulate a CTL-anti-tumour response.

Besides the data obtained from the studies on animal models, new evidence obtained from human breast tumour specimens revealed that the expression of p110δ becomes elevated during human breast cancer progression from grade I to grade III and that p110δ is highly expressed equally in infiltrated macrophages and cancer cells in breast carcinomas of grade III [113] (Table 1). These data further corroborate the hypothesis that p110δ has the potential to be an effective target for breast cancer treatment. A preclinical study which has been carried out by using a novel, highly selective PI3Kδ inhibitor, with the unique property of being ATP non-competitive, has shown very promising results [114] whereas a phase I clinical trial that was recently opened (NCT04328844) assesses the same p110δ inhibitor in patients with advanced or metastatic cancers. Interestingly, the gradually increased p110δ expression levels were found to correlate with a gradually reduced PTEN activity which was recovered and became elevated upon inhibition of p110δ [113]. Since PTEN somatic mutations are not very often in human breast cancers [98], this implies that the expression levels of p110δ could be used as a marker which will predict the response of tumours expressing wild type PTEN to therapy with p110δ inhibitors.

p110δ PI3K as an intrinsic cancer-causing driver in various solid tumours

Early work has suggested a role of p110δ in oncogenesis of non-haematopoietic cells by the first report showing that overexpression of wild-type p110δ led to hyperphosphorylation of Akt and to oncogenic transformation in avian fibroblasts [118]. Since then, further work has revealed new evidence that pointed to p110δ PI3K as an intrinsic cancer driver in various solid tumours in vitro and in vivo (Table 1).

A functional role for p110δ PI3K in prostate cancer was first indicated by a study showing that p110δ mRNA is increased in prostate carcinoma compared with normal prostate [119]. This finding was followed by the exploration of the role of p110δ PI3K in prostate cancer cell lines revealing that some prostate cell lines contain leucocyte levels of p110δ and that in those prostate cancer cell lines that express high p110δ levels and wild-type PTEN, p110δ dampens the activity of PTEN [54]. Pharmacological inactivation of p110δ led to increased PTEN activity and to reduced phosphorylation of Akt and cell proliferation [54] (Table 1).

Overexpression of p110δ PI3K was found in colon cancer tissues and colorectal cancer (CRC) cell lines and inhibition of p110δ expression by siRNA or p110δ activity by Idelalisib led to suppression of CRC cell growth, survival migration and invasion in vitro and to regression of tumour growth in vivo [120,121] (Table 1). In contrast, ectopic overexpression of PIK3CD significantly promoted CRC cell growth, Akt activity, migration and invasion in vitro and tumour growth in vivo [120]. It is of note that p110δ overexpression was found to correlate with advanced tumour stage, distant metastasis and overall patient survival [120] (Table 1).

The p110δ selective inhibitor Idelalisib was found to inhibit the growth of hepatocellular carcinoma (HCC) cells and to induce apoptosis in vitro as well as to suppress HCC-grafted tumour growth in vivo [122] (Table 1). In a chemical carcinogenesis model of liver malignancy p110δ activity was induced whereas suppression of p110δ expression or p110δ inactivation in these model cells led to inhibition of cell growth in vitro and to regression of grafted tumours in vivo [123]. Idelalisib markedly reduced cell viability and the phosphorylation of Akt in malignant hepatocytes derived from patients with GIII HCC whereas high p110δ expression levels in HCC patients were correlated with poor overall survival [123] (Table 1).

An impressive outcome had the treatment with Idelalisib of a patient with stage IV metastatic Merkel – Cell carcinoma, an often lethal without effective treatment type of skin cancer [124]. The tumour cells of this patient showed high expression of p110δ and treatment with Idelalisib led to a complete clinical response, without any substantial side effects [124] (Table 1).

Overexpression of p110δ mRNA and increased copy number of the PIK3CD gene were also found in some cases of glioblastoma [125,126]. Interestingly, resistance to erlotinib (an EGFR tyrosine kinase inhibitor) treatment has been associated with up-regulation of p110δ protein, whereas down-regulation of p110δ expression by siRNA restored the sensitivity to erlotinib in EGFR-amplified BS153 cells [127] (Table 1). However, it seems that p110α PI3K is also implicated in the regulation of growth and migration of glioblastoma cells since p110α has been detected in a panel of glioblastoma patient samples and inhibition of p110α activity was found to impair the anchorage-dependent growth of glioblastoma cells and to induce tumour regression in vivo [128].

Neuroblastoma is a cancer disease in which p110δ has been also implicated. Indeed, abnormally high p110δ expression levels were found in primary neuroblastoma tissue compared with the normal adrenal gland tissue [129] and suppression of p110δ expression in neuroblastoma cells led to impaired cell growth and survival [129] (Table 1). Studies from another group have shown that high p110δ protein levels correlate with low stage neuroblastomas whereas high p110α expression correlates with aggressive neuroblastomas [130]. The same group has shown that at the mRNA level, p110δ and p37δ (an alternatively spliced form of p110δ) were found at elevated levels in metastasizing neuroblastoma tumours compared with normal adrenal gland and that the expression of p37δ-mRNA was higher relatively to p110δ-mRNA in neuroblastoma non-survivor patients compared to survivors [131]

All these evidence imply that p110δ PI3K has an oncogenic potential that correlates with its expression levels.

Interplay between tumour cells and cells of the tumour microenvironment and a potential key role of p110δ PI3K inactivation in immune targeted therapies

Cancer growth could be likened as a group performance concert rather than a solo concert. Tumours consist of not only cancer cells but also multiple distinct cell types that are either resident or infiltrating host cells that interact with one another and comprise the tumour microenvironment (TME) [132]. TME is composed of stromal fibroblasts, extracellular matrix, blood and lymphatic vascular networks and immune cells that infiltrate the tumour stoma and include lymphocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs), and myeloid cells [133,134] (Figure 2). The interactions of cancer cells with cells of the TME determine the overall malignant progression and furthermore the therapeutic response of tumours [135]. Infiltrating cells can contribute positively as well as negatively to tumour progression by secreting chemokines, cytokines, growth factors and matrix-degrading enzymes inducing the invasion and proliferation of cancer cells or providing a structure that prevents tumour growth.

CD8+ cytotoxic T lymphocytes (CTLs) play a major role in anticancer immunity which is mediated by host anti-tumour immune responses [136,137]. CD8+ T cells recognize cognate antigens as the tumour develops and form metastases. T-cell receptor (TCR) engagement and cytokine signals lead to CTLs activation which is followed by initiation of T-cell proliferation and differentiation into an effector state. Subsequently, activated CTLs exert anti-tumour effects through secretion of interferon gamma (IFN-γ), tumour necrosis factor α (TNF-α) and granzymes along with other cytosolic effectors [136,138,139]. The process of CTLs activation leads not only to effector function but also to T-cell ‘exhaustion’ which is characterized by various features including the expression of inhibitory receptors and activation of inhibitory pathways that attenuate and terminate T-cell function [140,141]. The progressive loss of T-cell effector function is a physiological response in chronic infections and autoimmune diseases because it serves to diminish an excessive immune-mediated damage and prevent a rekindling of the disease as well as in the maintenance of self-tolerance [140,142,143]. However, in cancer, T cells ‘exhaustion’ hinders their anti-tumour efficacy [140].

A potent inhibitory immune check-point receptor that limits the response of activated CTLs is the programmed cell death 1 (PD-1), which belongs to the CD28/CTLA-4 family of the immunoglobulin superfamily [144]. PD-1 has two main ligands the PD-L1 (B7-H1) and PD-L2 (B7-DC) [144]. PD-1 is expressed at high levels on activated cells including T cells, B cells and natural killer (NK) cells whereas PD-L1 and PD-L2 are expressed on tumour cells and various immune cells including macrophages, monocytes, dendritic cells (DCs) and lymphocytes [144–149]. The activation of TCR induces the secretion of inflammatory cytokines including IFN-γ which then stimulate the expression of PD-L1 in target cells. The engagement of PD-L1 by PD-1 results in a PD-1-induced epigenetic program in T cells that attenuates T-cell proliferation, cytokine release and cytotoxic activity eventually leading to T-cell exhaustion which is a state of T-cell dysfunction while also promotes their apoptosis [142,150–152]. High expression levels of PD-L1 on tumour cells trigger an immune escape mechanism helping them to evade cytotoxic T cell mediated cell death [153].

Cytotoxic T Lymphocyte Associated Antigen-4 (CTLA-4) is another immune check-point receptor that is expressed on the surface of T cells following T-cell activation in response to antigen recognition. Up-regulation of CTLA-4 is associated with inhibition of immune signalling by T cells [154–156]. Due to high homology of CTLA-4 to the T cell co-stimulatory receptor CD28, CTLA-4 competitively binds to B7 molecules (CD80, CD86), expressed on the surface of antigen-presenting cells (APC) upon CD8+ T-cell receptor stimulation, leading to attenuation of T-cell immune response [156]. Since CD80 and CD86 are expressed on APCs, it is considered that CTLA-4 is involved in limiting the initiation of T-cell activation at early stages in the lymph nodes, where APCs present antigen to T cells for T-cell activation, and interferes with costimulation whereas PD-1 functions later on and limits T-cell response in the TME by dampening the signalling mediated by the TCR and negatively regulating antigen responsiveness [157–163].

Malignant progression can also be aided by the recruitment of other immunosuppressive elements such as regulatory T cells (Tregs), TAMs and myeloid-derived suppressor cells (MDSCs) which together with inhibitory cytokines and other stroma components compromise the T cell mediated anti-tumour immunity and act to diminish the anti-tumour response promoting tumour growth [136,138,164–166] (Figure 2). PD-1 expression up-regulates the conversion of naïve CD4+T cells to immunosuppressive Treg cells [167] which are a subpopulation of lymphocytes that suppress the activity of effector T cells by secreting IL-10 and TGF-β [138,168]. CTLA-4 is also constitutively expressed on Tregs and enhances their immunosuppressive activity [169–171].

TAMs are among the most abundant normal cells within the TME [172–175]. Growing evidence suggests that TAMs can drive tumour progression, metastasis and resistance to therapy and that TAMs can modulate tumour immunity including T-cell functions [176–189]. TAM-derived IL-6 and TNF-α consist factors that induce the survival of malignant cells and also promote resistance to chemotherapy and targeted agents [190]. TAMs have been implicated in all steps of metastasis including invasion, intravasation and extravasation [135]. CSF-1 which is secreted by neoplastic cells drives the expression of EGF by the CSF-1R signalling in macrophages and recruits macrophages to neoplastic tissue whereas EGF attracts tumour cells towards macrophages and through this paracrine pathway the invasion and intravasation of tumour cells in association with perivascular TAMs occurs [191–195] (Figure 2). A positive feedback pathway involving CCL2 has also been implicated in metastatic process [135] whereas CCL2 and CSF-1 are considered necessary to sustain macrophages numbers at tumour sites [176]. Macrophages also promote angiogenesis via production of VEGFA and other angiogenic factors and enhance the expression of VEGFA by endothelial cells [190].

TAMs promote immunosuppression by different mechanisms (Figure 2). Various stimuli such as cytokines and hypoxia [196,197] induce the expression of PD-L1 and B7-H4 in TAMs which then directly suppress the response of CTLs. Direct suppression of a CTL response can also occur via TAM secreted TGFβ which trascriptionally represses genes encoding cytokines and cytotoxins [198]. The killing functions of CTLs are also dampened indirectly by TAMs through recruitment of Tregs via CCL22 or through release of IL-10 which stimulates the expression of PD-L1 on DCs or inhibits the anti-tumour function of DCs by suppressing their capacity to produce IL-12 which acts to promote a Th1/CTL anti-tumour immune response [190,199,200]. TAMs also block the activity of CTLs through CTLs metabolic starvation which is mediated by overexpression of indoleamine 2,3-dioxygenase (IDO) (a tryptophan catabolic enzyme) and high arginase-1 (ARG) activity in TAMs that lead to local tryptophan shortage and depletion of L-arginine from the extracellular space [201].

The presence of MDSCs in the TME has also been shown to down-regulate the activity of CTLs and promote tumour tolerance [202]. MDSCs consist of heterogeneous populations of progenitor cells of both the mononuclear monocyte/DC lineage and progenitors of the neutrophils, granulocytes lineage [203]. Inflammatory monocyte and monocyte-related-mononuclear MDSCs infiltrate into malignant tissues and differentiate into TAMs [204,205]. Activated MDSCs secrete nitric oxide (NO) and reactive oxygen species and up-regulate the expression of arginase-1 (ARG) leading to depletion of L-arginine from the TME, induction of T cells cell-cycle arrest and T cells apoptosis [206–209]. PD-L1 is also expressed on human granulocytic MDSCs and interaction of PD-L1 with PD-1 on CTLs leads to T-cell exhaustion [210]. MDSCs also increase the secretion of anti-inflammatory cytokines, e.g. IL-10 and TGF-β and induce the activity of immunosuppressive Tregs impairing the anti-tumour activity of effector T cells [211,212] (Figure 2).

It is now well established that normal cells that comprise the TME can be co-opted and/or modified by tumours to secrete growth factors, chemokines, cytokines and matrix-degrating enzymes that finally induce the proliferation and invasion of cancer cells. Several studies have explored the regulation of checkpoint molecules, the roles of CTLs, and Tregs as well as the regulation of MDSCs, DCs and TAMs and have presented evidence showing that the enhancement of immune response or the simultaneously targeting of tumour cells and co-opted cells in the TME represent promising approaches for an effective treatment of cancer [213]. However, most of cells in the TME are balanced between tumour-inhibitory and tumour-promoting functions and play a major role in immune tolerance and on the other hand cancer cells are genetically unstable often gathering adaptive mutations. All these factors create limitations to multi-targeted therapies such as various adverse effects and drug resistance. The Nobel Prize committee in 2018 jointly awarded Dr James P. Allison and Dr Tasuku Honjo the Nobel Prize in Medicine or Physiology for their discovery of cancer therapy by inhibiting CTLA-4 and PD-1/PD-L1. The discovery of immune check-point inhibitors (ICIs) emerged a tremendous potential for new directions to cancer treatment [214–217]. The check-point inhibitors act by blocking check-point molecules such as CTLA-4 and PD-1 that dampen the activity of CTLs, allowing thus the adaptive immune system to respond to tumours. Therefore, the effectiveness of checkpoint inhibition depends on the presence of T cells in tumours or requires a modality to generate tumour specific T cells [218]. Monoclonal antibodies against CTLA-4 (Ipilimumab) and PD-1 (Nivolumab and Pembrolizumab) were the first immune checkpoint inhibitors to be approved in 2011 and 2014 respectively for use in patients with melanoma tumours [157]. The anti-PD-1 antibodies inhibit the interaction between PD-1 receptor and its ligand re-establishing thus the antitumor immunity [219,220]. Pharmacological blockade of the inhibitory PD-L1 ligand on tumour cells, stromal cells, TAMs and DCs has also been at the forefront of investigation for an efficient immunotherapy [221]. Blockade of PD-1/PD-L1 axis has been used to enhance anti-tumour immune response in the treatment of melanoma, non-small cell lung cancer (NSCLC) [222], bladder carcinoma [223,224], Hodgkin’s lymphoma [225,226] and Merkel cell carcinoma [227,228]. Blockade of CTLA-4 by anti-CTLA-4 antibodies promotes the expansion, cytokine secretion and cytotoxic activity of CTLs and inhibits the immunosuppressive activity of Tregs enhancing thus the CTL-mediated anti-tumour response [229].

The use of antibodies against CTLA-4, PD-1 or PD-L1 has shown significant anti-tumour effects and have revealed an impressive potential of immunotherapies for the treatment of various cancers [141,142,157,217,230,231]. However, in clinical practice, limitations that reduce the efficacy of such antibodies come from some important drawbacks to the use of ICIs including various adverse effects, drug resistance through innate and adaptive mechanisms and even poor responsiveness of the majority of patients in many cancers [168,232,233]. The function of CTLA-4 as an immune check-point molecule is to maintain immune regulation and self tolerance and therefore blockade of its pathways with CTLA-4 therapy leads to development of adverse effects as a result of autoimmune reactions [234–238]. Mechanisms of resistance to CTLA-4 blockade include the lack of the genes for response to IFN-γ (the molecule through which T cells exert their immune response) by some tumours [239] and the up-regulation of other checkpoint inhibitors when therapy with anti-CTLA-4 antibody is used leading thus to upregulation of a different pathway for inhibition of T cells [240]. Because of the dependence of CTLA-4 on the presence of costimulatory molecule B7 on tumour cells, lack of response to anti-CTLA-4 therapy might be a result of decreased immunogenicity of some tumours such as B16-BL6 melanoma which is very tumorigenic but not very immunogenic [241]. Blockade of PD-1/PD-L1 axis has become a promising therapy; however, more than 50% of patients with PD-L1 positive tumours show resistance or relapse after PD-1/PD-L1 blockade even if an initial response to therapy has occurred [242,243]. A variety of biological factors has been found to contribute to treatment resistance and poor responsiveness of cancer patients to anti-PD-1/PD-L1 therapies. An effective PD-1/PD-L1 blockade is almost entirely dependent on T-cell generation and function [244]. Thus, whether a tumour shows an inflamed or a noninflamed phenotype determines the effectiveness of PD-1/PD-L1 inhibitors which are more effective in inflamed tumours that express high PD-L1 levels and characterized by high CD8+ T-cell infiltration [242,245–247]. Other factors that mediate PD-1/PD-L1 blockade resistance include poor infiltration of T cells into tumours, lack of pre-existing and/or impaired activation of intra-tumoural T cells, lack of cancer antigens that are recognized by T cells, limited presentation of cancer-antigen, constitutive PD-L1 expression in cancer cells, mutations in IFN-γ signalling, activation of oncogenic pathways, and accumulation of immunosuppressive factors and cells in the TME including exhausted T cells, Tregs, MDSCs and TAMs [240,243,248]. Accumulating data indicate that MDSCs and TAMs reduce the effectiveness of immunotherapy [232,249,250] and especially for TAMs, which are amongst the most abundant non-transformed cells in the TME [172–175], several TAMs targeted strategies have presented evidence showing that the targeting of TAMs is able to potentiate the efficacy of check-point inhibitors [190,232,251].

Over the last years, mounting evidence have shown that the p110δ PI3K plays a seminal role in regulating directly or indirectly almost all cells of the TME as well as the cancer cells of some tumours [113,120–123,252,253] (Figure 2). p110δ inactivation in Tregs was found to impede the Treg-mediated suppression of anti-tumor immune response [254–256]. Beyond this, p110δ seems to act as a scale that keeps in balance the effect of Tregs and CD8+ T-cells on tumour growth. Indeed, although p110δ inhibition has been found to enhance the anti-tumour ability of effector T cells [257] and prevent tumour growth [258], p110δ inactivation has also been shown to disable CD8+ T-cell mediated cytotoxicity and to preferentially affects the proliferation, signalling and suppressive function of Tregs over CD8+ T cells [259] leading to an anti-tumour effect that mostly correlates with the dependence of the tumour on Treg-mediated immunosuppression [255]. Although most of the studies have assessed the role of p110γ in MDSCs [260–263] there is evidence to show that p110δ inhibition can also affect the number of infiltrating MDSCs and their function in the TME [254,264]. p110δ inhibitors can also stimulate an anti-cancer immune response by activating CDs to produce pro-inflammatory cytokines such as IL-12 which induces the CD8+ T-cell–mediated cytotoxic antitumor response [84,264,265]. TAMs are considered central drivers of tumour progression, metastasis and resistance to therapy [187–189] and p110δ PI3K has been emerged as a critical molecule that regulates the infiltrative capacity of macrophages and eventually the progression of breast cancer [113]. A compensatory link between CSF1R+ macrophages and Foxp3+ Treg cells has also been found in a colorectal cancer mouse model and a combined reduction in TAMs influx within tumours with inhibition of p110δ in Foxp3+ Treg cells resulted in a synergistic reduction in tumour growth pointed to the need of combined therapies as a more effective approach for the treatment of some cancers [256].

The evidence outlined above indicating that p110δ PI3K inhibition can shift the balance from immune tolerance towards effective anti-tumor immunity together with the recent data showing an impressive impact of p110δ inhibition on breast, liver and colorectal tumour growth in mice models and the respective correlation of p110δ overexpression with advanced tumour stage in patients with breast, liver and colorectal cancer [113,120–123] (Table 1) has emerged p110δ PI3K as an important therapeutic target in solid tumours. Preclinical studies and clinical trials have been undertaken to test p110δ selective inhibitors as a single agent treatment or in combinatorial regimens for the treatment of various solid tumours [114,266–272].

A series of studies with mouse models and preclinical studies have indicated that p110δ PI3K inhibitors could be used as potential therapeutic targets in combination with PD-1/PD-L1 or CTLA-4 blockade [114,266–273]. As it was mentioned above, PD-1 and CTLA-4 are up-regulated on CTLs and Tregs whereas Tregs constitutively express the highest levels of CTLA-4 within the tumour [148,274,275]. The principle receptors such as TCR and the co-stimulatory CD28 on these cells have been reported to signal through p110δ PI3K [40–49,276–280] and inactivation of p110δ has been found to reduce the number of peripheral Tregs and to impair the Treg-mediated tumour immunosuppression [254,259,281,282]. On the other hand, PD-1 inhibits T-cell function by activating SHP-2 phosphatase which leads to inhibition of the CD28-dependent PI3K activity [283–285], whereas CTLA-4 acts by eliminating the co-stimulatory signal through competitive binding to CD80 and CD86 ligands [286] and by antagonizing the activity of Akt through activation of the PP2A phosphatase abrogating thus the PI3K pathway [283]. Therefore, it seems reasonable one to expect that p110δ inhibition may not synergize with, but antagonize check-point blockade therapy since up-regulation of PD-1 and CTLA-4 check-point molecules down-regulate the p110δ PI3K signal while the respective check-point inhibitors act in part by enhancing PI3K activity which is in line with data showing that tumour models in mice with inactive p110δ were unresponsive to anti–CTLA-4 and anti–PD-L1 treatments [255]. However, combinatorial strategies using pharmacological inhibitors of p110δ and check-point inhibitors have shown very promising results [114,266–272]. A profound reason for this discrepancy might be the experimental model itself since in one case it is a genetic model of p110δ inactivation whereas in the other studies pharmacological inhibitors were used. Given that p110δ PI3K is needed in the early phase of CD8+ T-cell maturation whereas it is not necessary in activated cytotoxic CD8+ T cells [254], the time interval before the commence of p110δ inhibitor maybe enough for CD8+ T cells to encounter tumour antigens and become activated. Another explanation could be that the mechanism(s) by which p110δ PI3K inhibits the progression of tumours might not be complementary to, but rather distinct to that elicited by check-point inhibitors which intend to improve CD8+ T cell function. Our previous findings showing that p110δ PI3K plays a requisite role in macrophages for tumour progression and that breast tumour growth was abrogated in mice even in the absence of T cells [113] combined with results showing that the CSF1R+ macrophages and Foxp3+ Treg cells form a compensatory network [256] support this hypothesis. MDSCs also consist a suppressive cell population and their presence in the TME was shown to reduce the effectiveness of immunotherapy [249,250] whereas a combinatorial treatment with a specific inhibitor of p110δ/γ enhanced the therapeutic efficacy of PD-1 blockade in a osteosarcoma tumour model [268]. Therefore, strategies using a combinatorial targeted inactivation of p110δ in suppressive cell populations of the TME could be an alternative approach to enhance the effectiveness of immune check-point inhibitors that may offer a more efficient way to treat cancer.

Conclusions

While the relationship of p110δ PI3K with cancer had initially received less attention and p110δ had not been ranked high as a cancer target, the interest of many research groups was later on shifted towards haematologic cancers and p110δ PI3K was brought at the centre of attention in the field of haematologic malignancies [85–87,89,99]. Beyond any expectations, however, increasing evidence over the last decade has emerged p110δ PI3K as a key driver of solid tumour progression. p110δ PI3K seems to act as a highly potent oncogene by increasing its expression levels in a variety of solid tumours (Table 1). The correlation of the p110δ expression levels with the progression of human cancers implies that the p110δ expression should be considered as a prognostic marker for the response of tumour growth to p110δ inhibitors. This hypothesis is being studied and has led to promising results (Papakonstanti, unpublished data). The mechanisms that account for the up-regulation of p110δ expression in some cancer contexts while in others p110δ is expressed at very low levels (Table 1) are currently unknown. Such mechanisms may include differential transcriptional regulation in each cancer type or epigenetic aberrations whereas their delineation will make p110δ PI3K a more exploitable therapeutic target.

The remarkable impact of p110δ inhibition on breast tumour progression as a consequence of its efficacy to inhibit both, the survival and proliferation of cancer cells and the recruitment of macrophage to tumour sites (Figure 2) together with evidence showing that macrophages constitute 50% of the cell mass and correlate with poor prognosis in 80% of the breast cancer cases examined [192,287,288], make one reasonably expect that p110δ selective inhibitors have the potential to be clinically effective drugs for breast cancer treatment even as a single-agent treatment. Several studies, including preclinical studies and clinical trials have reported success with strategies assessing the effect of p110δ selective inhibitors as monotherapy or in combination with other therapeutic modalities such as immune check- point inhibitors [114,266–273].

In the last decade, we have witnessed major efforts in the understanding of the role of p110δ in solid tumours making us realize that there is important knowledge that has to be explored. It is impressive that the emerging importance of p110δ PI3K in various solid tumours derived not from classical oncogenic or tumour suppressor mutations, but from modulation of its expression levels. Further understanding of the functions and regulation of p110δ PI3K will mark a role for p110δ in cancer disease which will translate into therapeutic benefits. p110δ PI3K has come into the spotlight of solid tumours research and has the potential to become eminent in the field of solid tumours treatment.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

Authors’ work is supported by by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “First Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project Number: 3405) and by the Research Committee of the University of Crete [grant number KA 4720].

Abbreviations

     
  • CTLA-4

    cytotoxic T-lymphocyte antigen 4

  •  
  • CTL

    cytotoxic T lymphocyte

  •  
  • DC

    dendritic cell

  •  
  • MDSC

    myeloid-derived suppressor cell

  •  
  • PD-1

    programmed cell death-1

  •  
  • PD-L1

    programmed cell death-1 ligand

  •  
  • TAM

    tumour associated macrophage

  •  
  • TCR

    T-cell receptor

  •  
  • TME

    tumour microenvironment

  •  
  • Tregs

    regulatory T cells

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