CD8+ T cell infiltration into the tumor microenvironment has emerged to be a highly correlative and predictive marker for the response to checkpoint inhibition, in particular anti-PD1 therapy. Understanding the molecular mechanisms, that cause lack of T cell infiltration, will be instrumental for the development of novel treatment combination in order to overcome the lack of T cell accumulation in the tumor microenvironment. Recent studies have demonstrated that tumor cell-intrinsic signaling pathways, first and foremost the activation of the Wnt/β-catenin pathway, results in a lack of T cell infiltration in patients and genetically engineered mouse models (GEM). Using GEMs it was possible to identify that activation of the Wnt/β-catenin signaling pathway in primary tumors results in inhibited priming of tumor-antigen-specific T cells early. However, the question if activation of a tumor cell-intrinsic signaling pathways are capable to mediate secondary resistance remained unanswered. Furthermore, it is crucial to address if adoptive T cell transfer would be a potential therapeutic option for non-T cell inflamed tumors. By using GEM models with or without activation of the Wnt/β-catenin signaling pathway we identified that tumor cell-intrinsic activation of β-catenin signaling was capable to mediate secondary resistance by excluding T cells from the tumor microenvironment. Consistently, adoptive T cell transfer of antigen-specific T cells did not result in any therapeutic benefit in tumors with activated β-catenin signaling, an observation associated with lack of T cell infiltration. Using intravital- confocal microscopy we were able to identify that the few effector T cells found in β-catenin positive tumor failed to engage contact with tumor cells, while effector T cells in β-catenin negative tumors were capable to mediate tumor-eradication. Mechanistically, we identified a lack of effector chemokine (CXCL9, CXCL10) expression in tumors with activated β-catenin signaling. We found CD103+, Batf3-driven dendritic cells to be the predominant source of chemokines production, a subset of dendritic cells missing from β-catenin positive tumors. We further confirmed that this subtype of dendritic cells is both necessary and sufficient for effector T cell recruitment into the tumor microenvironment. In conclusion, our data support the notion that CD103+ dendritic cells within the tumor microenvironment are essential of effector T cell recruitment and mobility. Hence we propose that the combination of therapeutic regiment, allowing CD103+ dendritic cells accumulation and activation, with anti-PD1 checkpoint blockade should be synergistic in patients with lack of T cell-infiltration.
Citation Format: Stefani Spranger, Thomas F. Gajewski. T cell-mediated immune surveillance is inhibited by tumor-intrinsic signaling [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A104.
- ©2016 American Association for Cancer Research.