Abstract

Immunosuppression and the Anti-Tumor T cell Response in Natural Tumor Microenvironments

Nikhil Joshi, Assistant Professor, Yale University

Immunosuppressive regulatory T cells (T_regs) infiltrate many tumor types, and often this infiltration correlates with poor outcomes for patients. Most investigations of Treg function have focused on lymph nodes (LNs), where T_regs have many functions and suppress responses by many other immune cell types. For much of this regulation, the organized structure of the lymphoid tissue is critical, as T_regs must interact with cells to exert regulation. In the tumor microenvironment (TME) associated with established solid tumors in peripheral organs, like lung cancer however, it is less clear how T_regs regulate other cell types. Our laboratory uses immunocompetent, autochthonous genetically engineered mouse models to investigate T_reg function in tumors. Critically, these models recapitulate many aspects of the native TME as tumors develop, facilitating investigations into the impacts of the TME on immune cell function. We found increased numbers of T_regs in lungs of mice with lung adenocarcinomas, but surprisingly nearly all of these Tregs were in in tumor-associated tertiary lymphoid structures (TA-TLSs) that formed during tumor development. TA-TLSs had been observed in early-stage non-small cell lung cancer patients, but they had not been detected in mouse tumor models and their functions remain understudied. TA-TLSs are associated with 93% of the tumors in our model and are histologically similar to TA-TLSs in lung adenocarcinoma patients. TA-TLSs in our model function like tumor-associated LNs, recruiting activated tumor-specific CD8 T cells from the circulation and facilitating their interactions with tumor-antigen presenting dendritic cells (DCs). However, despite this capacity of TA-TLSs to stimulate anti-tumor responses, advanced tumors were free of infiltrating lymphocytes. This is due in part to immuno-suppressive mechanisms in TA-TLSs, as acute genetic depletion of T_regs in TA-TLSs unlea