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 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, using the autochthonous Braf/PTEN model of melanoma, modified to express OVA as a tumor-specific antigen, we show that CD103+ TRM-like cells orchestrate the initial antitumor immune response, which is hindered by infiltration of regulatory T (Treg) cells. By longitudinal CyCIF and flow cytometry analysis we found that TRM-like cells rapidly filled a stable niche in the tumor. TRM-like cells were phenotypically and transcriptionally distinct, 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, activation of TRM-like CD8+ TILs, substantial CD8+ and CD4+ T cell infiltration, and a decrease in tumor growth. Deletion of CD8+ T cells prior to Treg depletion blunted T cell recruitment to the tumor. Together, these data suggest early tumor immune escape is mediated by Tregs suppressing TRM immunosurveillance and T cell recruitment.