17. Jason Williams, PhD

Tissue-resident memory T (TRM) cells have emerged as key players and potential immunotherapeutic targets in antitumor immunity. However, the study of TRM cells within the TME has been hampered by a lack of adequate tumor models. Cell lines injected subcutaneously do not contain the same biological cues as tumors arising from the dermis and epidermis, while most other models lack a known tumor-specific antigen to track immune responses. We have addressed these two issues by modifying the genetically engineered Braf/PTEN model of melanoma to express OVA as a tumor antigen. Longitudinal analysis revealed that CD103+ TRM-like cells composed a majority of CD8+ TILs in nascent tumors, but this population steadily declined over time. The CD103+ TRM-like subset was phenotypically unique, expressing low levels of the inhibitory receptors PD1 and Tim3 and unique co-expression of CD101. CyCIF analysis revealed co-localization of CD103+ regulatory T (Treg) cells in nascent tumors. Transient depletion of Treg cells led to a decrease in tumor growth, ~100-fold augmentation of the OVA-specific antitumor immune response, a ~7-fold increase in CD8+ TILs, and activation of CD103+ CD8+ TRM-like TILs. FTY720 was administered after Treg depletion to discern between systemic and local effects, which revealed significant T cell tumor infiltration and local activation of CD103+ TRM-like cells. Together, these data indicate that the earliest stages of tumor immune escape may be orchestrated by regulatory T cells and their suppression of the initial antitumor TRM cell insult.