Tissue specific cues govern melanoma specific resident memory CD8+ T cell persistence in skin and tumor draining lymph nodes 2310174

Abstract

Abstract Introduction CD8+ resident memory (Trm) cells are key sentinels of anti tumor immunity, residing durably in tissues and rapidly responding to cognate antigen. We identified melanoma specific Trm cells in skin and tumor draining lymph nodes (tdLN) that protect against metastasis, yet the mechanisms governing their maintenance, spatial organization and heterogeneity remain unclear. Methods Using a B16 induced vitiligo model, we generated gp100 specific CD69+CD103+ Trm cells in skin and tdLNs. Xenium spatial transcriptomics in wild type and β2m conditional knockout mice mapped endogenous and antigen specific Trm cells niches and tested antigen dependence. Conditional T cell receptor alpha (TCR) knockout mice and IL7/IL15 blocking antibodies probed the roles of TCR signaling and homeostatic cytokines. Results High resolution spatial transcriptomics revealed distinct micro-environments for Trm cells in skin and TdLNs. Skin Trm cells clustered with epidermal and hair follicle keratinocytes, whereas TdLN-Trm cells preferentially contacted dendritic cells, antigen presenting B cells, fibroblastic reticular cells and sub-capsular sinus macrophages. This heterogeneity prompted the hypothesis that tissue specific cues govern Trm cell survival. Consistent with this, conditional loss of MHC-I signaling significantly reduced tdLN-Trm cells but spared skin-Trm, a finding confirmed in inducible TCR knockout mice. Blocking IL7 and IL15 significantly reduced Trm cell proportions in both tissues, indicating that while antigen presentation sustains Trm cells in lymph nodes (LN), IL7/IL15 signaling is critical for their survival in both skin and LNs. Conclusion Our investigations show that melanoma specific Trm cells interact with different cellular partners in skin vs. tdLN niches, underscoring the influence of local microenvironment on their survival cues. We reveal Trm residence in LNs requires ongoing antigen presentation, and that both skin and tdLN Trm populations depend on a shared IL7/IL15 cytokine axis for maintenance. Funding Source R01CA254042 and R01CA225028A Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)