Regulatory T cells inhibit CD8+ TRM-like cells during the early stages of tumor immune escape

Tissue-resident memory T (TRM) cells are increasingly recognized as crucial components of tumor immunosurveillance and potential targets in cancer immunotherapy. However, studying TRM cells within the tumor microenvironment (TME) has been challenging due to limitations in existing tumor models. Traditional cell lines injected subcutaneously fail to replicate the biological cues of dermal and epidermal tumors, and many genetically engineered mouse models (GEMMs) lack a specific tumor antigen for tracking immune responses. Here, we use an autochthonous Braf/PTEN model of melanoma, modified to express OVA as a tumor-specific model antigen, to show that CD103+ TRM-like cells orchestrate the initial antitumor immune response and this response is antagonized by infiltration of regulatory T (Treg) cells. Longitudinal spatial profiling (cyclic immunofluorescence) and flow cytometry analysis of Braf/PTEN/OVA mice show that TRM-like cells rapidly fill a stable niche in the tumor. These TRM-like cells are phenotypically and transcriptionally distinct from other T cells, expressing low levels of PD-1 and Tim-3, but uniquely expressed CD101 and GzmB. Depletion of Treg cells led to augmentation of the OVA-specific antitumor immune response involving activation of TRM-like CD8+ TILs, substantial CD8+ and CD4+ T cell infiltration, and a decrease in tumor growth. Depletion of CD8+ T cells prior to Treg depletion blunted T cell recruitment to the tumor. These data show that immune escape is mediated by the ability of Tregs to suppress early antitumor responses and T cell recruitment by TRM-like cells.