Regulatory T cells Restrain CD4 T Cell Control of MHC-I-Deficient Metastatic Pancreatic Cancer Emerging After PD-L1 Blockade [ATAC-seq]

We investigate mechanisms of immunotherapy resistance in pancreatic cancer. PD-L1 blockade selected for metastatic tumor variants with defective IFN-g–inducible MHC-I due to epigenetic Tap1 silencing. Restoration of MHC-I limited primary tumor growth but failed to prevent metastasis. In contrast, regulatory T cell (TREG) depletion abrogated metastasis by unleashing conventional CD4 T cells. Metastasis was also mitigated by transfer of tumor-reactive CD4 T cells or by CTLA-4 blockade. Tumor-specific CD4 T cells adopt a TCF1⁺SLAMF6⁺ progenitor state in lymph nodes and further differentiate in malignant sites. CTLA4 blockade abrogated metastasis, drove intratumoral accumulation CD4 T cells with stemness and tissue residency features, producing a gene signature correlating with improved patient outcomes. MHC-I restoration with anti-CTLA4 prolonged animal survival. TREG and CD4 T cells co-localized in human tumors and abundance correlated with tumor MHC-I and overall survival. Together, these findings identify actionable mechanisms of immune evasion and metastasis in immunotherapy-resistant cancer.