The recent successes of cancer immunotherapy, first and foremost checkpoint blockade therapy, illustrate the power of the immune system to control cancer. As the number of patients receiving this therapy is increasing, the number of patients being resistant or establishing resistance toward immunotherapy is also increasing. We, therefore, need to further understand the mechanisms mediate resistance in order to prevent or overcome those mechanisms. Increasing evidence is being reported that alterations in tumor cell-intrinsic signaling pathways, including the activation of the WNT/β-catenin pathway, are associated with blunted T-cell infiltration. Infiltration of tumor by CD8 T cells is one of the most predictive biomarkers for the response toward immunotherapy and therefore the notion that alterations of certain tumor cell-intrinsic signaling pathways might mediate resistance should be considered. Understanding the molecular and immunological mechanisms mediating resistance will ultimately facilitate the development of effective treatment strategies counteracting immune evasion.

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