Growing evidence has emerged that subgroups of cancer patients have a spontaneous T cell-centered immune response reflected by infiltration of antigen-specific CD8+ T cells into the tumor microenvironment. However, another major subgroup of patients completely lacks this phenotype. Importantly, the presence of tumor-infiltrating CD8+ T cells has been correlated with clinical response to anti-PD-1 mAb and other immunotherapies. Recent work from our laboratory has revealed that activation of the Wnt/β-catenin pathway within tumor cells can mediate exclusion of T cells from the tumor microenvironment. Using an autochthonous inducible mouse model for melanoma (BrafV600E/PTEN-/-; BP) combined with or without stabilized β-catenin (BrafV600E/PTEN-/-/CAT-STA; BPC) we were able to show that this exclusion of antigen specific T cells from the tumor microenvironment was due to failed recruitment of Batf3-lineage dendritic cells. The absence of these dendritic cells led to defective early T cell priming and absence of systemic immunity. However, whether tumor-intrinsic β-catenin signaling might mediate tumor resistance at the effector phase of the anti-tumor immune response or even after an anti-tumor T cell response was established is not known. To test this notion, we used the regressor tumor model MC57-SIY, which is spontaneously rejected and leads to immunologic memory that can mediate immune surveillance. These tumors were implanted into naïve BP and BPC mice that had been crossed to a Rosa26-LSL-SIY inducible antigen mouse. Following complete regression of the primary (MC57.SIY) tumor, the genetically induced melanomas were induced by topical tamoxifen application and tumor growth kinetics as well as infiltration of antigen-specific T cells analyzed. Although the primary SIY-specific CD8+ T cell response and the induced memory response were comparable between both tumor models, tumor protection was observed against BP-SIY tumors but not BPC-SIY tumors. This increased tumor control in BP-SIY mice was accompanied by strong T cell infiltration and a boosted memory response. These results suggest that effector T cell migration into tumor sites also might be excluded via tumor-intrinsic β-catenin signaling. To test this notion directly, we activated SIY-reactive T cell receptor transgenic T cells (2C T cells) in vitro and adoptively transferred them into BP-SIY and BPC-SIY tumor-bearing hosts. In fact, primed 2C cells were only found in BP-SIY tumors but not BPC-SIY tumors. These results were confirmed using in vivo 2-photon microscopy of the tumor microenvironment. Taken together, these data provide strong evidence that up-regulation of β-catenin in tumor cells is a very potent mechanism of immune evasion even after a primary immune response has been induced. As such, mechanisms of immune surveillance and editing of tumors expand beyond selection at the level of antigens but additionally via specific oncogene pathways activated within the tumor cells. Moreover, tumor-intrinsic β-catenin activation likely mediates resistance not only to checkpoint blockade therapy but also to T cell adoptive transfer.

Citation Format: Stefani Spranger, Brendan Horton, Thomas F. Gajewski. Immune surveillance is thwarted by tumor-cell intrinsic β-catenin signaling. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B154.