Immune oncology (IO) is challenged to expand its usefulness to a broader range of cancers. A second generation of IO agents acting beyond the realm of Checkpoint Inhibitor Therapy (CIT) is sought with the intent of turning immune-resistant cancers into appealing IO targets. The published literature proposes a profusion of models to explain cancer immune resistance to CIT that largely outnumber the immune landscapes and corresponding resistance mechanisms. In spite of the complex and contradicting models suggested to explain refractoriness to CIT, the identification of prevailing mechanisms and their targeting may not be as daunting as it at first appears. Here, we suggest that cancer cells go through a conserved evolutionary bottleneck facing a Two-Option Choice to evade recognition by the immune competent host: they can either adopt a clean oncogenic process devoid of immunogenic stimuli (immune-silent tumors) or display an entropic biology prone to immune recognition (immune-active tumors) but resilient to rejection thanks to the recruitment of compensatory immune suppressive processes. Strategies aimed at enhancing the effectiveness of CIT will be different according to the immune landscape targeted.

Immune oncology (IO) is urged to expand the usefulness of Checkpoint Inhibitor Therapy (CIT) to a broader range of refractory cancers [13]. In spite of the variety of models proposed to explain cancer immune resistance, the identification of prevailing mechanisms and their targeting may not be as daunting as it at first appears [4] as long as answers are sought following a well-designed and systematic strategy; to quote Jonas Salk: ‘the answer to biological problems preexists, it is the question that needs to be discovered’ [5]. A survey of open access data from The Cancer Genome Atlas (TCGA) comprising four histotypes (breast, lung, colon carcinoma and melanoma) indicated that cancer cells go through a conserved evolutionary bottleneck facing a Two-Option Choice (TOC) to evade immune recognition by the immune competent host: they can either adopt a clean oncogenic process devoid of immunogenic stimuli (immune-silent tumors) or display an entropic biology prone to immune recognition (immune-active tumors) but resilient to rejection thanks to the recruitment of compensatory immune suppressive processes [3]. We refer to the first option as Primary Immune Resistance (PIRes) and to the second as Compensatory Immune Resistance (CIRes). These two landscapes may influence refractoriness to CIT through entirely distinct mechanisms. In addition, Secondary Immune Resistance (SIRes) may ensue as an escape mechanism following originally successful treatment. Finally, we refer to False-Immune Resistance in those cases in which treatment could not be completed due to limiting toxicity.

To explain the distinct landscapes and the respective reasons determining immune refractoriness to CIT, a wealth of observational and/or experimental models has been advocated that largely outnumber the three phenotypes of human cancer (Table 1). The current series presents some of the salient models that propose a targetable mechanism regulating the growth of cancer in the immune competent host, primarily focusing on immune regulatory control of cancer within the immune-active landscapes. However, this review will lean toward the discussion of potential strategies to immune convert silent tumors into immune-active ones, therefore, offering a window of opportunity for IO agents that would otherwise be unlikely to affect an immune-silent environment where innate resistance dominates.

Table 1
Salient models explaining cancer immune landscapes and pertinent literature
 References ICR group 
WNT/β−Catenin [6,7Depleted 
MAPK hypothesis [8Depleted 
Immunogenic cell death [9,10,11Active 
Regulatory T cells [12,13Active 
IL23-Th17 axis [1418Active 
Myeloid suppressor cells [19Active 
PI3K-γ signature [2024Depleted 
IDO/NOS signature [2527Ubiquitous 
SGK1 signature [28,29Depleted 
Shc1 signature [30Depleted 
Barrier molecules [31,32Depleted 
Mesenchymal transition [3335Depleted 
Cancer-associated fibroblasts [3640Ubiquitous 
TAM receptor tyrosine kinases [4145Active 
Hypoxia/adenosine suppression [46,47Active 
TREX1 clearance of cytosolic DNA [4850NA 
Checkpoint cluster [51,52Active 
Oncogene addiction [53,54Depleted 
Epigenetic regulation [5558Depleted 
Regulatory B cells [59Active 
NF-κB activation [60 
 References ICR group 
WNT/β−Catenin [6,7Depleted 
MAPK hypothesis [8Depleted 
Immunogenic cell death [9,10,11Active 
Regulatory T cells [12,13Active 
IL23-Th17 axis [1418Active 
Myeloid suppressor cells [19Active 
PI3K-γ signature [2024Depleted 
IDO/NOS signature [2527Ubiquitous 
SGK1 signature [28,29Depleted 
Shc1 signature [30Depleted 
Barrier molecules [31,32Depleted 
Mesenchymal transition [3335Depleted 
Cancer-associated fibroblasts [3640Ubiquitous 
TAM receptor tyrosine kinases [4145Active 
Hypoxia/adenosine suppression [46,47Active 
TREX1 clearance of cytosolic DNA [4850NA 
Checkpoint cluster [51,52Active 
Oncogene addiction [53,54Depleted 
Epigenetic regulation [5558Depleted 
Regulatory B cells [59Active 
NF-κB activation [60 

We recently proposed a theory that unifies current models of cancer immune resistance into a Theory of Everything (TOE) assigning each of them to a specific immune landscape according to their transcriptional expression pattern [3]. This conclusion was based on a survey of two open access datasets comprising ∼3000 cases of breast cancer [3,8,61]. A nomenclature was proposed to define cancers according to their immune contexture ranking them according to the transcriptional expression of genes associated with Immune-mediated Tissue-specific Destruction (ITD). ITD is a conserved mechanism responsible for destructive flares of autoimmunity, acute allograft rejection, and graft-versus-host disease, clearance of pathogen-infected cells and rejection of cancer [62,63]. A signature representative of the ITD was selected from a larger set of interferon (IFN)-γ-induced transcripts named the Immunologic Constant of Rejection (ICR) [62]. The ICR bears both predictive and prognostic implications within a continuum of anticancer immune surveillance [64] and includes four functional categories: CXCR3/CCR5 chemokines (CXCL9, CXCL10 and CCL5), Th1 signaling (IFNG, IL12B, TBX21, CD8A, STAT1, IRF1 and CD8B), effector (GNLY, PRF1, GZMA, GZMB and GZMH) and immune regulatory (CD274, CTLA4, FOXP3, IDO1 and PDCD1) functions. The expression of the 20 representative genes is highly correlated with the extended ICR signature that includes ∼500 genes [62,63,65]. It has been conclusively shown that responsiveness to CIT is observed almost exclusively in the immune-active landscape and is predetermined by a conducive microenvironment [35,66,67]. However, while the immune-active landscape is a prerequisite, it is not sufficient alone to predict immune response.

This concept was described originally by our group in 2002 in the context of other types of immunotherapy, including response to antigen-specific vaccination administered in combination with systemic interleukin-2 [68], and subsequently validated in the context of systemic interleukin-2 administration [69] and the adoptive transfer of tumor-infiltrating lymphocytes [70]. Therefore, immune responsiveness is promiscuous to treatment and it is multifactorial with the tumor microenvironment, playing a permissive but not exclusive role [71].

The 20-gene ICR signatures bear strong analogy with other IFN-γ-dependent signatures predictive of immune responsiveness to interleukin-2-based therapies [6870] and CIT [66]. Thus, we used these 20 genes as surrogate biomarkers to define immune landscapes more or less likely to be susceptible to CIT. The expression pattern of the 20 ICR genes defined four cancer immune landscapes that were segregated from ICR1 to ICR4 according to the crescendo of expression of ICR transcripts. ICR1 and ICR2 represent various degrees of immune depletion, while ICR3 and ICR4 demonstrate rising levels of expression of ICR genes. For the purpose of discussion, the four landscapes were conflated conceptually into immune-silent or immune-active clusters.

Subsequently, a selection of transcripts reported in association with various cancer immune resistance models was collated into a signature meant to unify within a single study the hallmarks of cancer immune biology (Table 1). We refer to this collection as the TOE signatures of resistance (sRes) and used it to define the geographical distribution of each model within immune landscapes.

We observed that most transcripts representative of immune regulatory mechanisms tightly correlated in expression with the ICR and TIS (tumor inflammation signature), suggesting that immune suppression goes hand-in-hand with immune activation [3].

Based on this analysis of breast cancer data, we hypothesized that immune-silent tumors evolve by employing a strictly essential interface of interactions with the host's stromal cells that exclude immune cell recognition. This may be due to the development of a cancer cell cycle that avoids Immunogenic Cell Death (ICD) or by the downstream induction of biochemical or mechanical barriers that hamper immune infiltration. Thus, these ‘clean’ tumors evolve through the promotion of cancer cells that adopt refined growth mechanisms reduced to the bare necessities of life. Indeed, similar observations could be corroborated by the analysis of another three cancer histotypes including lung, colon carcinomas and melanoma (Figure 1).

Consistency of immune resistance signature expression across different.

Figure 1.
Consistency of immune resistance signature expression across different.

Mapping gene signatures according to their expression in different immune landscapes of breast (BRCA), lung (LUAD) and colon (COAD) carcinoma, and melanoma (SKCM); in red are signatures selectively expressed in the immune-active (ICR4) landscape, in blue those selectively expressed in the immune-silent (ICR1) landscape and in white those that are ubiquitously expressed independent of immune landscape.

Figure 1.
Consistency of immune resistance signature expression across different.

Mapping gene signatures according to their expression in different immune landscapes of breast (BRCA), lung (LUAD) and colon (COAD) carcinoma, and melanoma (SKCM); in red are signatures selectively expressed in the immune-active (ICR4) landscape, in blue those selectively expressed in the immune-silent (ICR1) landscape and in white those that are ubiquitously expressed independent of immune landscape.

This hypothesis is corroborated by the observation that these tumors (1) are transcriptionally dormant compared with the immune-active ones and (2) bear low prevalence of mutations in oncogenes suggesting a more orderly growth process [8]. It is, therefore, reasonable to suppose that clean tumor growth is dependent on a stepwise oncogenic mechanism that avoids immune recognition [7274]. Thus, we propose that the natural history of cancer is shaped at the cross-road of two biologies by a ‘TOC’ or Hobson's predicament: (1) immunogenic tumors can only survive in the host when immune suppressive mechanisms balance the reaction of the host and (2) silent tumors can grow undisturbed.

Here, we suggest that interference of a clean oncogenic pathway may result not only in cancer cell death but also in the disruption of its biology leading to less pristine processes conducive to ICD and allowing, therefore, a window of opportunity for IO agents [911,7595].

This concept is based on the premise that cancer is fundamentally a cell biology problem with cancer cells orchestrating and directing their surroundings. Therefore, efforts aiming at altering the tumor microenvironment should primarily be directed toward the disruption of intrinsic cancer cell processes. A best example of the central role played by cancer cells in determining their surroundings is the Patient-Derived Xenograft (PDX) model; after three passages in immune-deficient mice, the mouse stromal cells completely replace the human, yet the original architecture of the cancer is maintained [9698]. A second premise is that the immune environment of cancer is driven by a cascade of innate mechanisms (first signal), while the adaptive immune response requires signals initiated by the innate immune system that inform about the origin of the antigen and the type of response to be induced as described by Charles A. Janeway and by Polly Matzinger's Danger Model [83,99108].

The leading role played by ICD in driving the immune landscape of cancer is counteracted by lines of thought that promote priming of adaptive immune responses by non-self-antigens (neo-antigens) generated by the translation of missense mutations into novel protein domains. This hypothesis is based on several experimental [109,110] as well as the clinical observation that cancers with high mutational burden are more frequently associated with the immune-active landscape and consequently with responsiveness to CIT [33,98,109]. This concept has been, however, questioned by recent observations by our [8] and others' groups [111]. Moreover, basic understanding of immunologic processes confutes the primary role that adaptive immunity plays in the rejection of cancer in the absence of a first initiating signal [99104,107]. The conditionality of adaptive immune responses is suggested by experimental evidence that they are not an essential requirement for the rejection of cancer as exemplified by the transferrable anticancer innate immunity model [112115] and by oncotropic virus-mediated immune rejection of xenografts in immune-deficient mice [116,117]. From the clinical standpoint, the secondary role played by adaptive immunity could also explain the paradoxical observation that vaccines aimed at priming adaptive immune responses can consistently elicit systemic immunity, which, however, does not correlate with tumor rejection [118,119]. It could be postulated that because of the adjuvants used in vaccine administration, at the site of vaccination the afferent loop of the adaptive immune response can be initiated stimulating chemoattraction and antigen presentation. However, at the tumor site, in the absence of a strong innate immunity-mediated chemoattraction, the efferent loop languishes mostly because of lack of trafficking on vaccine-induced cancer-specific T cells to the target tissue. It should also be pointed out that seminal studies done on the effectiveness of tumor-infiltrating lymphocytes demonstrated that their homing at the tumor site is necessary, though not sufficient, to induce tumor regression, emphasizing the critical role that chemoattraction plays in immune responsiveness [120]. In turn, chemoattraction of circulating T cells is tightly dependent on the expression of CXCR3- and CCR5-binding chemokines that are expressed in response to innate immune activation as a component of the ICR signature. Finally, it has been recently shown that the intra-lesional injection of oncolytic virus can turn an immune-silent tumor into an immunogenic one with activation of innate signals that secondarily attracts adaptive immune responses [121].

Thus, we believe that the prospect for IO therapy is to segregate future efforts according to immune landscapes and respective cause for refractoriness to CIT. It is likely that cancers displaying immune-activated landscapes and associated CIRes will benefit from combination of various IO agents that could shift the balance in favor of immune-effector over immune regulatory mechanisms. On the other hand, silent cancers will need to be primed to stir ICD and subsequent recruitment of innate and adaptive immune cells that could become suitable targets for IO agents including CIT.

Summary
  • Immune suppression goes hand-in-hand with immune activation.

  • Immune-active tumors include almost exclusively all the immune regulatory mechanisms to counterbalance their immunogenicity.

  • Immune-silent tumors are enriched of signatures that reflect activation of oncogenic mechanisms and exclude immune regulatory mechanism.

  • Human cancers go through a conserved evolutionary bottleneck facing a two-option choice to evade immune recognition by the immune competent host: they either adopt a clean oncogenic process devoid of immunogenic stimuli or display an entropic biology prone to immune recognition but resilient to rejection thanks to the recruitment of compensatory immune suppressive processes.

  • Immunotherapy agents including check point inhibitors work only on the immune-active tumors enriched of immune regulatory mechanisms.

  • Immune-silent tumors need to be targeted with agents that can disrupt their lean biology and induce immunogenic cell death.

Abbreviations

     
  • CIRes

    compensatory immune resistance

  •  
  • CIT

    checkpoint inhibitor therapy

  •  
  • ICD

    immunogenic cell death

  •  
  • ICR

    Immunologic Constant of Rejection

  •  
  • IFN

    interferon

  •  
  • IO

    immune oncology

  •  
  • ITD

    immune-mediated tissue-specific destruction

  •  
  • TCGA

    The Cancer Genome Atlas

  •  
  • TLR

    Toll-like receptor

  •  
  • TOC

    Two-Option Choice

  •  
  • TOE

    Theory of Everything

Competing Interests

All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.

References

References
1
Emens
,
L.A.
,
Ascierto
,
P.A.
,
Darcy
,
P.K.
,
Demaria
,
S.
,
Eggermont
,
A.M.M.
,
Redmond
,
W.L.
et al
(
2017
)
Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape
.
Eur. J. Cancer
81
,
116
129
2
Ascierto
,
P.A.
and
McArthur
,
G.A.
(
2017
)
Checkpoint inhibitors in melanoma and early phase development in solid tumors: what's the future?
J. Transl. Med.
15
,
173
3
Turan,
T.
,
Kannan,
D.
,
Patel,
M.
,
Barnes,
M.J.
,
Tanlimco,
S.G.
,
Lu,
R.
et al
(
2017
)
Immune oncology, immune responsiveness and the theory of everything
.
J. Immunother. Cancer
In press
4
Rees
,
J.
(
2002
)
Complex disease and the new clinical sciences
.
Science
296
,
698
700
5
Salk
,
J.
(
1969
)
Immunological paradoxes: theoretical considerations in the rejection or retention of grafts, tumors, and normal tissue
.
Ann. N.Y. Acad. Sci.
164
,
365
380
6
Spranger
,
S.
,
Bao
,
R.
and
Gajewski
,
T.F.
(
2015
)
Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity
.
Nature
523
,
231
235
7
Corrales
,
L.
,
Matson
,
V.
,
Flood
,
B.
,
Spranger
,
S.
and
Gajewski
,
T.F.
(
2017
)
Innate immune signaling and regulation in cancer immunotherapy
.
Cell Res.
27
,
96
108
8
Hendrickx,
W.
,
Simeone,
I.
,
Anjum,
S.
,
Mokrab,
Y.
,
Bertucci,
F.
,
Finetti,
P.
et al
(
2017
)
Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis
.
Oncoimmunology
6
,
e1253654
9
Galluzzi
,
L.
,
Buqué
,
A.
,
Kepp
,
O.
,
Zitvogel
,
L.
and
Kroemer
,
G.
(
2017
)
Immunogenic cell death in cancer and infectious disease
.
Nat. Rev. Immunol.
17
,
97
111
10
Wegner
,
K.W.
,
Saleh
,
D.
and
Degterev
,
A.
(
2017
)
Complex pathologic roles of RIPK1 and RIPK3: moving beyond necroptosis
.
Trends Pharmacol. Sci.
38
,
202
225
11
Matt
,
S.
and
Hofmann
,
T.G.
(
2016
)
The DNA damage-induced cell death response: a roadmap to kill cancer cells
.
Cell Mol. Life Sci.
73
,
2829
2850
12
Abd Al Samid
,
M.
,
Chaudhary
,
B.
,
Khaled
,
Y.S.
,
Ammori
,
B.J.
and
Elkord
,
E.
(
2016
)
Combining FoxP3 and Helios with GARP/LAP markers can identify expanded Treg subsets in cancer patients
.
Oncotarget
7
,
14083
14094
13
Elkord
,
E.
,
Abd Al Samid
,
M.
and
Chaudhary
,
B.
(
2015
)
Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP
.
Oncotarget
6
,
20026
20036
14
Tosolini
,
M.
,
Kirilovsky
,
A.
,
Mlecnik
,
B.
,
Fredriksen
,
T.
,
Mauger
,
S.
,
Bindea
,
G.
et al
(
2011
)
Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer
.
Cancer Res.
71
,
1263
1271
15
Coccia
,
M.
,
Harrison
,
O.J.
,
Schiering
,
C.
,
Asquith
,
M.J.
,
Becher
,
B.
,
Powrie
,
F.
et al
(
2012
)
IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells
.
J. Exp. Med.
209
,
1595
1609
16
Kirchberger
,
S.
,
Royston
,
D.J.
,
Boulard
,
O.
,
Thornton
,
E.
,
Franchini
,
F.
,
Szabady
,
R.L.
et al
(
2013
)
Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model
.
J. Exp. Med.
210
,
917
931
17
Alinejad
,
V.
,
Dolati
,
S.
,
Motallebnezhad
,
M.
and
Yousefi
,
M.
(
2017
)
The role of IL17B-IL17RB signaling pathway in breast cancer
.
Biomed. Pharmacother.
88
,
795
803
18
Ngiow
,
S.F.
,
Teng
,
M.W.L.
and
Smyth
,
M.J.
(
2013
)
A balance of interleukin-12 and -23 in cancer
.
Trends Immunol.
34
,
548
555
19
Munn
,
D.H.
and
Bronte
,
V.
(
2016
)
Immune suppressive mechanisms in the tumor microenvironment
.
Curr. Opin. Immunol.
39
,
1
6
20
De Henau
,
O.
,
Rausch
,
M.
,
Winkler
,
D.
,
Campesato
,
L.F.
,
Liu
,
C.
,
Cymerman
,
D.H.
et al
(
2016
)
Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells
.
Nature
539
,
443
447
21
Kaneda
,
M.M.
,
Messer
,
K.S.
,
Ralainirina
,
N.
,
Li
,
H.
,
Leem
,
C.J.
,
Gorjestani
,
S.
et al
(
2016
)
PI3Kγ is a molecular switch that controls immune suppression
.
Nature
539
,
437
442
22
Daragmeh
,
J.
,
Barriah
,
W.
,
Saad
,
B.
and
Zaid
,
H.
(
2016
)
Analysis of PI3K pathway components in human cancers
.
Oncol. Lett.
11
,
2913
2918
PMID:
[PubMed]
23
Liu
,
P.
,
Cheng
,
H.
,
Roberts
,
T.M.
and
Zhao
,
J.J.
(
2009
)
Targeting the phosphoinositide 3-kinase pathway in cancer
.
Nat. Rev. Drug Discov.
8
,
627
644
24
Karlsson
,
E.
,
Veenstra
,
C.
,
Emin
,
S.
,
Dutta
,
C.
,
Pérez-Tenorio
,
G.
,
Nordenskjöld
,
B.
et al
(
2015
)
Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer
.
Breast Cancer Res. Treat.
153
,
31
40
25
Munn
,
D.H.
and
Mellor
,
A.L.
(
2016
)
IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance
.
Trends Immunol.
37
,
193
207
26
Liu
,
Q.
,
Tomei
,
S.
,
Ascierto
,
M.L.
,
De Giorgi
,
V.
,
Bedognetti
,
D.
,
Dai
,
C.
et al
(
2014
)
Melanoma NOS1 expression promotes dysfunctional IFN signaling
.
J. Clin. Invest.
124
,
2147
2159
27
Mondanelli
,
G.
,
Ugel
,
S.
,
Grohmann
,
U.
and
Bronte
,
V.
(
2017
)
The immune regulation in cancer by the amino acid metabolizing enzymes ARG and IDO
.
Curr. Opin. Pharmacol.
35
,
30
39
28
Di Cristofano
,
A.
(
2017
)
SGK1: the dark side of PI3K signaling
.
Curr. Top. Dev. Biol.
123
,
49
71
29
Xiaobo
,
Y.
,
Qiang
,
L.
,
Xiong
,
Q.
,
Zheng
,
R.
,
Jianhua
,
Z.
,
Zhifeng
,
L.
et al
(
2016
)
Serum and glucocorticoid kinase 1 promoted the growth and migration of non-small cell lung cancer cells
.
Gene
576
(
1 Pt 2
),
339
346
30
Ahn
,
R.
,
Sabourin
,
V.
,
Bolt
,
A.M.
,
Hébert
,
S.
,
Totten
,
S.
,
De Jay
,
N.
et al
(
2017
)
The Shc1 adaptor simultaneously balances Stat1 and Stat3 activity to promote breast cancer immune suppression
.
Nat. Commun.
8
,
14638
31
Salerno
,
E.P.
,
Bedognetti
,
D.
,
Mauldin
,
I.S.
,
Deacon
,
D.H.
,
Shea
,
S.M.
,
Pinczewski
,
J.
et al
(
2016
)
Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk
.
Oncoimmunology
5
,
e1240857
32
Buckanovich
,
R.J.
,
Facciabene
,
A.
,
Kim
,
S.
,
Benencia
,
F.
,
Sasaroli
,
D.
,
Balint
,
K.
et al
(
2008
)
Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy
.
Nat. Med.
14
,
28
36
33
Hugo
,
W.
,
Zaretsky
,
J.M.
,
Sun
,
L.
,
Song
,
C.
,
Moreno
,
B.H.
,
Hu-Lieskovan
,
S.
et al
(
2016
)
Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma
.
Cell
165
,
35
44
34
Shields
,
B.D.
,
Mahmoud
,
F.
,
Taylor
,
E.M.
,
Byrum
,
S.D.
,
Sengupta
,
D.
,
Koss
,
B.
et al
(
2017
)
Indicators of responsiveness to immune checkpoint inhibitors
.
Sci. Rep.
7
,
807
35
Herbst
,
R.S.
,
Soria
,
J.-C.
,
Kowanetz
,
M.
,
Fine
,
G.D.
,
Hamid
,
O.
,
Gordon
,
M.S.
et al
(
2014
)
Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
.
Nature
515
,
563
567
36
Feig
,
C.
,
Jones
,
J.O.
,
Kraman
,
M.
,
Wells
,
R.J.B.
,
Deonarine
,
A.
,
Chan
,
D.S.
et al
(
2013
)
Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer
.
Proc. Natl. Acad. Sci. U.S.A.
110
,
20212
20217
37
Kraman
,
M.
,
Bambrough
,
P.J.
,
Arnold
,
J.N.
,
Roberts
,
E.W.
,
Magiera
,
L.
,
Jones
,
J.O.
et al
(
2010
)
Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α
.
Science
330
,
827
830
38
Öhlund
,
D.
,
Elyada
,
E.
and
Tuveson
,
D.
(
2014
)
Fibroblast heterogeneity in the cancer wound
.
J. Exp. Med.
211
,
1503
1523
39
Ohlund
,
D.
,
Handly-Santana
,
A.
,
Biffi
,
G.
,
Elyada
,
E.
,
Almeida
,
A.S.
,
Ponz-Sarvise
,
M.
et al
(
2017
)
Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
.
J. Exp. Med.
214
,
579
596
PMID:
[PubMed]
40
Özdemir
,
B.C.
,
Pentcheva-Hoang
,
T.
,
Carstens
,
J.L.
,
Zheng
,
X.
,
Wu
,
C.-C.
,
Simpson
,
T.R.
et al
(
2014
)
Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival
.
Cancer Cell
25
,
719
734
41
Crittenden
,
M.R.
,
Baird
,
J.
,
Friedman
,
D.
,
Savage
,
T.
,
Uhde
,
L.
,
Alice
,
A.
et al
(
2016
)
Mertk on tumor macrophages is a therapeutic target to prevent tumor recurrence following radiation therapy
.
Oncotarget
7
,
78653
78666
PMID:
[PubMed]
42
Akalu
,
Y.T.
,
Rothlin
,
C.V.
and
Ghosh
,
S.
(
2017
)
TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy
.
Immunol. Rev.
276
,
165
177
43
Zhang
,
B.
,
Fang
,
L.
,
Wu
,
H.-M.
,
Ding
,
P.-S.
,
Xu
,
K.
and
Liu
,
R.-Y.
(
2016
)
Mer receptor tyrosine kinase negatively regulates lipoteichoic acid-induced inflammatory response via PI3K/Akt and SOCS3
.
Mol. Immunol.
76
,
98
107
44
Grabiec
,
A.M.
and
Hussell
,
T.
(
2016
)
The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation
.
Semin. Immunopathol.
38
,
409
423
45
Crittenden
,
M.R.
,
Cottam
,
B.
,
Savage
,
T.
,
Nguyen
,
C.
,
Newell
,
P.
and
Gough
,
M.J.
(
2012
)
Expression of NF-κB p50 in tumor stroma limits the control of tumors by radiation therapy
.
PLoS ONE
7
,
e39295
46
Hatfield
,
S.M.
and
Sitkovsky
,
M.
(
2016
)
A2a adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer
.
Curr. Opin. Pharmacol.
29
,
90
96
47
Hu
,
C.-J.
,
Wang
,
L.-Y.
,
Chodosh
,
L.A.
,
Keith
,
B.
and
Simon
,
M.C.
(
2003
)
Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation
.
Mol. Cell Biol.
23
,
9361
9374
48
Demaria
,
S.
,
Golden
,
E.B.
,
Formenti
,
S.C.
(
2015
)
Role of local radiation therapy in cancer immunotherapy
.
JAMA Oncol.
1
,
1325
1332
49
Vanpouille-Box
,
C.
,
Diamond
,
J.M.
,
Pilones
,
K.A.
,
Zavadil
,
J.
,
Babb
,
J.S.
,
Formenti
,
S.C.
et al
(
2015
)
TGFbeta is a master regulator of radiation therapy-induced antitumor immunity
.
Cancer Res.
75
,
2232
2242
50
Vanpouille-Box,
C.
,
Alard,
A.
,
Aryankalayil,
M.J.
,
Sarfraz,
Y.
,
Diamond,
J.M.
,
Schneider,
R.J.
et al
(
2017
)
DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity
.
Nat. Commun.
8
,
15618
51
Benci
,
J.L.
,
Xu
,
B.
,
Qiu
,
Y.
,
Wu
,
T.J.
,
Dada
,
H.
,
Twyman-Saint Victor
,
C.
et al
(
2016
)
Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade
.
Cell
167
,
1540
1554.e12
52
Koyama
,
S.
,
Akbay
,
E.A.
,
Li
,
Y.Y.
,
Herter-Sprie
,
G.S.
,
Buczkowski
,
K.A.
,
Richards
,
W.G.
et al
(
2016
)
Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints
.
Nat. Commun.
7
,
10501
53
Gainor
,
J.F.
,
Shaw
,
A.T.
,
Sequist
,
L.V.
,
Fu
,
X.
,
Azzoli
,
C.G.
,
Piotrowska
,
Z.
et al
(
2016
)
EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis
.
Clin. Cancer Res.
22
,
4585
4593
54
Akbay
,
E.A.
,
Koyama
,
S.
,
Carretero
,
J.
,
Altabef
,
A.
,
Tchaicha
,
J.H.
,
Christensen
,
C.L.
et al
(
2013
)
Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors
.
Cancer Discov.
3
,
1355
1363
55
Place
,
A.E.
,
Jin Huh
,
S.
and
Polyak
,
K.
(
2011
)
The microenvironment in breast cancer progression: biology and implications for treatment
.
Breast Cancer Res.
13
,
227
56
Adeegbe
,
D.O.
,
Liu
,
Y.
,
Lizotte
,
P.H.
,
Kamihara
,
Y.
,
Aref
,
A.R.
,
Almonte
,
C.
et al
(
2017
)
Synergistic immunostimulatory effects and therapeutic benefit of combined histone deacetylase and bromodomain inhibition in non-small cell lung cancer
.
Cancer Discov.
7
,
852
867
PMID:
[PubMed]
57
Guerriero
,
J.L.
,
Sotayo
,
A.
,
Ponichtera
,
H.E.
,
Castrillon
,
J.A.
,
Pourzia
,
A.L.
,
Schad
,
S.
et al
(
2017
)
Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages
.
Nature
543
,
428
432
58
Mondino
,
A.
,
Vella
,
G.
and
Icardi
,
L.
(
2017
)
Targeting the tumor and its associated stroma: One and one can make three in adoptive T cell therapy of solid tumors
.
Cytokine Growth Factor Rev.
36
,
57
65
PMID:
[PubMed]
59
Saleh
,
S.M.I.
,
Bertos
,
N.
,
Gruosso
,
T.
,
Gigoux
,
M.
,
Souleimanova
,
M.
,
Zhao
,
H.
et al
(
2017
)
Identification of interacting stromal axes in triple-negative breast cancer
.
Cancer Res.
77
,
4673
4683
60
Hopewell
,
E.L.
,
Zhao
,
W.
,
Fulp
,
W.J.
,
Bronk
,
C.C.
,
Lopez
,
A.S.
,
Massengill
,
M.
et al
(
2013
)
Lung tumor NF-κB signaling promotes T cell-mediated immune surveillance
.
J. Clin. Invest.
123
,
2509
2522
61
Miller
,
L.D.
,
Chou
,
J.A.
,
Black
,
M.A.
,
Print
,
C.
,
Chifman
,
J.
,
Alistar
,
A.
et al
(
2016
)
Immunogenic subtypes of breast cancer delineated by gene classifiers of immune responsiveness
.
Cancer Immunol. Res.
4
,
600
610
62
Wang
,
E.
,
Worschech
,
A.
and
Marincola
,
F.M.
(
2008
)
The immunologic constant of rejection
.
Trends Immunol.
29
,
256
262
63
Spivey
,
T.L.
,
Uccellini
,
L.
,
Ascierto
,
M.L.
,
Zoppoli
,
G.
,
De Giorgi
,
V.
,
Delogu
,
L.G.
et al
(
2011
)
Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis
.
J. Transl. Med.
9
,
174
64
Galon
,
J.
,
Angell
,
H.K.
,
Bedognetti
,
D.
and
Marincola
,
F.M.
(
2013
)
The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures
.
Immunity
39
,
11
26
65
Panelli
,
M.C.
,
Stashower
,
M.E.
,
Slade
,
H.B.
,
Smith
,
K.
,
Norwood
,
C.
,
Abati
,
A.
et al
(
2007
)
Sequential gene profiling of basal cell carcinomas treated with imiquimod in a placebo-controlled study defines the requirements for tissue rejection
.
Genome Biol.
8
,
R8
66
Ayers
,
M.
,
Lunceford
,
J.
,
Nebozhyn
,
M.
,
Murphy
,
E.
,
Loboda
,
A.
,
Kaufman
,
D.R.
et al
(
2017
)
IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade
.
J. Clin. Invest.
127
,
2930
2940
PMID:
[PubMed]
67
Tumeh
,
P.C.
,
Harview
,
C.L.
,
Yearley
,
J.H.
,
Shintaku
,
I.P.
,
Taylor
,
E.J.M.
,
Robert
,
L.
et al
(
2014
)
PD-1 blockade induces responses by inhibiting adaptive immune resistance
.
Nature
515
,
568
571
68
Wang
,
E.
,
Miller
,
L.D.
,
Ohnmacht
,
G.A.
,
Mocellin
,
S.
,
Perez-Diez
,
A.
,
Petersen
,
D.
et al
(
2002
)
Prospective molecular profiling of melanoma metastases suggests classifiers of immune responsiveness
.
Cancer Res.
62
,
3581
3586
PMID:
[PubMed]
69
Weiss
,
G.R.
,
Grosh
,
W.W.
,
Chianese-Bullock
,
K.A.
,
Zhao
,
Y.
,
Liu
,
H.
,
Slingluff
, Jr,
C.L.
et al
(
2011
)
Molecular insights on the peripheral and intratumoral effects of systemic high-dose rIL-2 (aldesleukin) administration for the treatment of metastatic melanoma
.
Clin. Cancer Res.
17
,
7440
7450
70
Bedognetti
,
D.
,
Spivey
,
T.L.
,
Zhao
,
Y.
,
Uccellini
,
L.
,
Tomei
,
S.
,
Dudley
,
M.E.
et al
(
2013
)
CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2
.
Br. J. Cancer
109
,
2412
2423
71
Wang
,
E.
,
Uccellini
,
L.
and
Marincola
,
F.M.
(
2012
)
A genetic inference on cancer immune responsiveness
.
Oncoimmunology
1
,
520
525
72
Spranger
,
S.
and
Gajewski
,
T.F.
(
2015
)
A new paradigm for tumor immune escape: β-catenin-driven immune exclusion
.
J. Immunother. Cancer
3
,
43
73
Spranger
,
S.
,
Sivan
,
A.
,
Corrales
,
L.
and
Gajewski
,
T.F.
(
2016
)
Tumor and host factors controlling antitumor immunity and efficacy of cancer immunotherapy
.
Adv. Immunol.
130
,
75
93
74
Sweis
,
R.F.
,
Spranger
,
S.
,
Bao
,
R.
,
Paner
,
G.P.
,
Stadler
,
W.M.
,
Steinberg
,
G.
et al
(
2016
)
Molecular drivers of the non-T-cell-inflamed tumor microenvironment in urothelial bladder cancer
.
Cancer Immunol. Res.
4
,
563
568
75
Galluzzi
,
L.
,
Buqué
,
A.
,
Kepp
,
O.
,
Zitvogel
,
L.
and
Kroemer
,
G.
(
2015
)
Immunological effects of conventional chemotherapy and targeted anticancer agents
.
Cancer Cell
28
,
690
714
76
Galluzzi
,
L.
,
Vacchelli
,
E.
,
Bravo-San Pedro
,
J.M.
,
Buqué
,
A.
,
Senovilla
,
L.
,
Baracco
,
E.E.
et al
(
2014
)
Classification of current anticancer immunotherapies
.
Oncotarget
5
,
12472
12508
77
Garg,
A.D.
,
Galluzzi,
L.
,
Apetoh,
L.
,
Baert,
T.
,
Birge,
R.B.
,
Bravo-San Pedro,
J.M.
et al
(
2015
)
Molecular and translational classifications of DAMPs in immunogenic cell death
.
Front. Immunol.
6
,
588
PMID:
[PubMed]
78
Hannani
,
D.
,
Sistigu
,
A.
,
Kepp
,
O.
,
Galluzzi
,
L.
,
Kroemer
,
G.
and
Zitvogel
,
L.
(
2011
)
Prerequisites for the antitumor vaccine-like effect of chemotherapy and radiotherapy
.
Cancer J.
17
,
351
358
79
Kepp
,
O.
,
Galluzzi
,
L.
,
Giordanetto
,
F.
,
Tesniere
,
A.
,
Vitale
,
I.
,
Martins
,
I.
et al
(
2009
)
Disruption of the PP1/GADD34 complex induces calreticulin exposure
.
Cell Cycle
8
,
3971
3977
80
Kepp
,
O.
,
Galluzzi
,
L.
,
Martins
,
I.
,
Schlemmer
,
F.
,
Adjemian
,
S.
,
Michaud
,
M.
et al
(
2011
)
Molecular determinants of immunogenic cell death elicited by anticancer chemotherapy
.
Cancer Metastasis Rev.
30
,
61
69
81
Kepp
,
O.
,
Galluzzi
,
L.
,
Zitvogel
,
L.
and
Kroemer
,
G.
(
2010
)
Pyroptosis - a cell death modality of its kind?
Eur. J. Immunol.
40
,
627
630
82
Kepp
,
O.
,
Senovilla
,
L.
,
Vitale
,
I.
,
Vacchelli
,
E.
,
Adjemian
,
S.
,
Agostinis
,
P.
et al
(
2014
)
Consensus guidelines for the detection of immunogenic cell death
.
Oncoimmunology
3
,
e955691
83
Kroemer
,
G.
,
Galluzzi
,
L.
,
Kepp
,
O.
and
Zitvogel
,
L.
(
2013
)
Immunogenic cell death in cancer therapy
.
Annu. Rev. Immunol.
31
,
51
72
84
Ma
,
Y.
,
Adjemian
,
S.
,
Mattarollo
,
S.R.
,
Yamazaki
,
T.
,
Aymeric
,
L.
,
Yang
,
H.
et al
(
2013
)
Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells
.
Immunity
38
,
729
741
85
Ma
,
Y.
,
Adjemian
,
S.
,
Yang
,
H.
,
Catani
,
J.P.P.
,
Hannani
,
D.
,
Martins
,
I.
et al
(
2013
)
ATP-dependent recruitment, survival and differentiation of dendritic cell precursors in the tumor bed after anticancer chemotherapy
.
Oncoimmunology
2
,
e24568
86
Ma
,
Y.
,
Yamazaki
,
T.
,
Yang
,
H.
,
Kepp
,
O.
,
Galluzzi
,
L.
,
Zitvogel
,
L.
et al
(
2013
)
Tumor necrosis factor is dispensable for the success of immunogenic anticancer chemotherapy
.
Oncoimmunology
2
,
e24786
87
Martins
,
I.
,
Kepp
,
O.
,
Galluzzi
,
L.
,
Senovilla
,
L.
,
Schlemmer
,
F.
,
Adjemian
,
S.
et al
(
2010
)
Surface-exposed calreticulin in the interaction between dying cells and phagocytes
.
Ann. N.Y. Acad. Sci.
1209
,
77
82
88
Martins
,
I.
,
Michaud
,
M.
,
Sukkurwala
,
A.Q.
,
Adjemian
,
S.
,
Ma
,
Y.
,
Shen
,
S.
et al
(
2012
)
Premortem autophagy determines the immunogenicity of chemotherapy-induced cancer cell death
.
Autophagy
8
,
413
415
89
Martins
,
I.
,
Wang
,
Y.
,
Michaud
,
M.
,
Ma
,
Y.
,
Sukkurwala
,
A.Q.
,
Shen
,
S.
et al
(
2014
)
Molecular mechanisms of ATP secretion during immunogenic cell death
.
Cell Death Differ.
21
,
79
91
90
Menger
,
L.
,
Vacchelli
,
E.
,
Adjemian
,
S.
,
Martins
,
I.
,
Ma
,
Y.
,
Shen
,
S.
et al
(
2012
)
Cardiac glycosides exert anticancer effects by inducing immunogenic cell death
.
Sci. Transl. Med.
4
,
143ra99
91
Michaud
,
M.
,
Martins
,
I.
,
Sukkurwala
,
A.Q.
,
Adjemian
,
S.
,
Ma
,
Y.
,
Pellegatti
,
P.
et al
(
2011
)
Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice
.
Science
334
,
1573
1577
92
Sukkurwala
,
A.Q.
,
Adjemian
,
S.
,
Senovilla
,
L.
,
Michaud
,
M.
,
Spaggiari
,
S.
,
Vacchelli
,
E.
et al
(
2014
)
Screening of novel immunogenic cell death inducers within the NCI mechanistic diversity set
.
Oncoimmunology
3
,
e28473
93
Sukkurwala
,
A.Q.
,
Martins
,
I.
,
Wang
,
Y.
,
Schlemmer
,
F.
,
Ruckenstuhl
,
C.
,
Durchschlag
,
M.
et al
(
2014
)
Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8
.
Cell Death Differ.
21
,
59
68
94
Zitvogel
,
L.
,
Galluzzi
,
L.
,
Kepp
,
O.
,
Smyth
,
M.J.
and
Kroemer
,
G.
(
2015
)
Type I interferons in anticancer immunity
.
Nat. Rev. Immunol.
15
,
405
414
95
Zitvogel
,
L.
,
Kepp
,
O.
,
Galluzzi
,
L.
and
Kroemer
,
G.
(
2012
)
Inflammasomes in carcinogenesis and anticancer immune responses
.
Nat. Immunol.
13
,
343
351
96
Maykel
,
J.
,
Liu
,
J.H.
,
Li
,
H.
,
Shultz
,
L.D.
,
Greiner
,
D.L.
and
Houghton
,
J.
(
2014
)
NOD-scidIl2rg tm1Wjl and NOD-Rag1 null Il2rg tm1Wjl: a model for stromal cell-tumor cell interaction for human colon cancer
.
Dig. Dis. Sci.
59
,
1169
1179
97
Schietinger
,
A.
,
Philip
,
M.
and
Schreiber
,
H.
(
2008
)
Specificity in cancer immunotherapy
.
Semin. Immunol.
20
,
276
285
98
Blankenstein
,
T.
,
Leisegang
,
M.
,
Uckert
,
W.
and
Schreiber
,
H.
(
2015
)
Targeting cancer-specific mutations by T cell receptor gene therapy
.
Curr. Opin. Immunol.
33
,
112
119
99
Janeway
, Jr,
C.A.
(
2013
)
Pillars article: approaching the asymptote? Evolution and revolution in immunology
.
J. Immunol.
191
,
4475
4487
PMID:
[PubMed]
100
Janeway
, Jr,
C.A.
(
1989
)
Approaching the asymptote? Evolution and revolution in immunology
.
Cold Spring Harb. Symp. Quant. Biol.
54
(
Pt 1
),
1
13
101
Janeway
, Jr,
C.A.
and
Medzhitov
,
R.
(
1998
)
Introduction: the role of innate immunity in the adaptive immune response
.
Semin. Immunol.
10
,
349
350
102
Medzhitov
,
R.
and
Janeway
, Jr,
C.A.
(
1997
)
Innate immunity: the virtues of a nonclonal system of recognition
.
Cell
91
,
295
298
103
Medzhitov
,
R.
and
Janeway
, Jr,
C.A.
(
1997
)
Innate immunity: impact on the adaptive immune response
.
Curr. Opin. Immunol.
9
,
4
9
104
Fuchs
,
E.J.
and
Matzinger
,
P.
(
1996
)
Is cancer dangerous to the immune system?
Semin. Immunol.
8
,
271
280
105
Fuchs
,
E.J.
and
Matzinger
,
P.
(
1992
)
B cells turn off virgin but not memory T cells
.
Science
258
,
1156
1159
106
Fuchs
,
E.J.
,
Ridge
,
J.P.
and
Matzinger
,
P.
(
1996
)
Response: immunological tolerance
.
Science
272
,
1406
1408
107
Matzinger
,
P.
(
2002
)
An innate sense of danger
.
Ann. N.Y. Acad. Sci.
961
,
341
342
108
Matzinger
,
P.
(
1998
)
An innate sense of danger
.
Semin. Immunol.
10
,
399
415
109
Gubin
,
M.M.
,
Zhang
,
X.
,
Schuster
,
H.
,
Caron
,
E.
,
Ward
,
J.P.
,
Noguchi
,
T.
et al
(
2014
)
Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens
.
Nature
515
,
577
581
110
Ward
,
J.P.
,
Gubin
,
M.M.
and
Schreiber
,
R.D.
(
2016
)
The role of neoantigens in naturally occurring and therapeutically induced immune responses to cancer
.
Adv. Immunol.
130
,
25
74
111
Spranger
,
S.
,
Luke
,
J.J.
,
Bao
,
R.
,
Zha
,
Y.
,
Hernandez
,
K.M.
,
Li
,
Y.
et al
(
2016
)
Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma
.
Proc. Natl. Acad. Sci. U.S.A.
113
,
E7759
E7E68
112
Cui
,
Z.
,
Willingham
,
M.C.
,
Hicks
,
A.M.
,
Alexander-Miller
,
M.A.
,
Howard
,
T.D.
,
Hawkins
,
G.A.
et al
(
2003
)
Spontaneous regression of advanced cancer: identification of a unique genetically determined, age-dependent trait in mice
.
Proc. Natl. Acad. Sci. U.S.A.
100
,
6682
6687
113
Hicks
,
A.M.
,
Riedlinger
,
G.
,
Willingham
,
M.C.
,
Alexander-Miller
,
M.A.
,
Von Kap-Herr
,
C.
,
Pettenati
,
M.J.
et al
(
2006
)
Transferable anticancer innate immunity in spontaneous regression/complete resistance mice
.
Proc. Natl. Acad. Sci. U.S.A.
103
,
7753
7758
114
Hicks
,
A.M.
,
Willingham
,
M.C.
,
Du
,
W.
,
Pang
,
C.S.
,
Old
,
L.J.
and
Cui
,
Z.
(
2006
)
Effector mechanisms of the anti-cancer immune responses of macrophages in SR/CR mice
.
Cancer Immun.
6
,
11
PMID:
[PubMed]
115
Riedlinger
,
G.
,
Adams
,
J.
,
Stehle
, Jr,
J.R.
,
Blanks
,
M.J.
,
Sanders
,
A.M.
,
Hicks
,
A.M.
et al
(
2010
)
The spectrum of resistance in SR/CR mice: the critical role of chemoattraction in the cancer/leukocyte interaction
.
BMC Cancer
10
,
179
116
Worschech
,
A.
,
Chen
,
N.
,
Yu
,
Y.A.
,
Zhang
,
Q.
,
Pos
,
Z.
,
Weibel
,
S.
et al
(
2009
)
Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facet of oncolytic therapy
.
BMC Genomics
10
,
301
117
Worschech
,
A.
,
Haddad
,
D.
,
Stroncek
,
D.F.
,
Wang
,
E.
,
Marincola
,
F.M.
and
Szalay
,
A.A.
(
2009
)
The immunologic aspects of poxvirus oncolytic therapy
.
Cancer Immunol. Immunother.
58
,
1355
1362
118
Lee
,
K.H.
,
Panelli
,
M.C.
,
Kim
,
C.J.
,
Riker
,
A.I.
,
Bettinotti
,
M.P.
,
Roden
,
M.M.
et al
(
1998
)
Functional dissociation between local and systemic immune response during anti-melanoma peptide vaccination
.
J. Immunol.
161
,
4183
4194
PMID:
[PubMed]
119
Lee
,
K.H.
,
Wang
,
E.
,
Nielsen
,
M.B.
,
Wunderlich
,
J.
,
Migueles
,
S.
,
Connors
,
M.
et al
(
1999
)
Increased vaccine-specific T cell frequency after peptide-based vaccination correlates with increased susceptibility to in vitro stimulation but does not lead to tumor regression
.
J. Immunol.
163
,
6292
6300
PMID:
[PubMed]
120
Pockaj
,
B.A.
,
Sherry
,
R.M.
,
Wei
,
J.P.
,
Yannelli
,
J.R.
,
Carter
,
C.S.
,
Leitman
,
S.F.
et al
(
1994
)
Localization of 111indium-labeled tumor infiltrating lymphocytes to tumor in patients receiving adoptive immunotherapy. Augmentation with cyclophosphamide and correlation with response
.
Cancer
73
,
1731
1737
PMID:
[PubMed]
121
Ribas
,
A.
,
Dummer
,
R.
,
Puzanov
,
I.
,
VanderWalde
,
A.
,
Andtbacka
,
R.H.I.
,
Michielin
,
O.
et al
(
2017
)
Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy
.
Cell
170
,
1109
1119.e10
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