Factors governing CD8+ resident memory (Trm) cell retention and migration in tumors and draining lymph nodes 2260863

Abstract Introduction CD8+ resident memory (Trm) cells are critical mediators of anti-tumor immunity. However, it remains unclear whether canonical memory T cell features, namely antigen independence and durable persistence, apply to Trm cells that persist amid chronic antigen exposure in tumors and tumor draining lymph nodes (TDLNs). A better understanding of these features will allow us to interpret durable responses against cancer, while advancing our fundamental knowledge of Trm biology. Methods We employed the B2905 (M4) mouse melanoma model and inducible TCR-alpha knockout mice to assess whether antigen engagement is required for CD103+CD69+ Trm cell retention within the tumor and the TDLN. Xenium spatial transcriptomics was used to define patterns of Trm cell localization within these tissues. Mice expressing the KAEDE photoconvertible marker were used to track Trm cell egress from tumors. Results The retention of Trm cells within tumors occurred independently of antigen engagement, whereas antigen recognition was required for Trm persistence within TDLNs. Spatial transcriptomics further supported this conclusion, as melanoma antigen-specific CD8 T cells localized in regions lacking cognate antigen exhibited a stronger Trm transcriptional signature than those in antigen-expressing areas. Tracking T cell migratory dynamics, we found that Trm cells are less likely to migrate from the tumor to the TDLN than non-Trm cells. Conclusion These studies establish that intratumoral Trm cells, like canonical memory T cells, persist and are maintained in an antigen-independent manner, whereas Trm cells in TDLNs are antigen-dependent. Additionally, we found that differential T cell — antigen localization patterns within tumors may affect their Trm characteristics. Ongoing studies will determine how the spatial proximity to antigen governs Trm cell retention, migration, and their capacity to protect against metastatic disease. Funding Source NCI R01 CA225028 and R01 CA120777. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)