Skin mites enhance virtual memory T cell responses against immune checkpoint inhibitor-resistant tumors 2304047

Abstract Introduction Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet some patients remain non-responsive. The current study aims to investigate the role of complex microbiota and commensals across body sites in this response. Methods Because traditional laboratory mouse models are limited by their lack of complex, natural microbiota, we explored ICI therapy in a colony of ‘wildling’ mice, the founders of which were generated by re-deriving C57BL/6 embryos in wild mice. Results Wildling mice significantly enhanced CD8 T cell—dependent antitumor responses upon ICI, in comparison to conventional laboratory mice on the same genetic background. This enhanced anti-tumor activity required IFN-γ and CXCR3—CXCL9/10—mediated recruitment of CXCR3+ CD49d⁻ virtual memory (TVM) CD8+ T cells. Wildling mice had markedly expanded, highly functional TVM cells across lymphoid and non-lymphoid tissues, with heightened effector signatures, increased cytokine responsiveness, and superior intratumoral accumulation upon ICI treatment. Screening of natural microbiota and commensals revealed that skin mites induced the wildling phenotype. Transfer of skin mites to conventional laboratory mice induced a substantial expansion of CD49d⁻ TVM cells and ICI responsiveness, whereas depletion of mites from wildling mice reduced both TVM abundance and ICI efficacy. Analysis of public databases demonstrated increased abundance of CD8 T cells with a TVM transcriptional signature correlated with melanoma of ICI responders, supporting the translational relevance of these findings. Conclusion This study identifies skin mite—driven expansion of CD49d⁻ TVM cells in anti-tumor immunity and ICI responsiveness. These findings offer new insights into targeting skin mites and Tvm as a strategy to overcome resistance to ICIs in cancer treatment. Funding Source Intramural research programs of NIDDK, NIH Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)