| First Author | Schmiechen ZC | Year | 2026 |
| Journal | Sci Immunol | Volume | 11 |
| Issue | 120 | Pages | eadz4302 |
| PubMed ID | 42361199 | Mgi Jnum | J:393116 |
| Mgi Id | MGI:8409488 | Doi | 10.1126/sciimmunol.adz4302 |
| Citation | Schmiechen ZC, et al. (2026) T(reg) cells promote immunotherapy-induced immune evasion by restraining CD4 T cell control of MHC-I-deficient metastatic pancreatic cancer. Sci Immunol 11(120):eadz4302 |
| abstractText | Mechanisms driving immunotherapy resistance in pancreatic cancer are poorly defined. We demonstrate that programmed death-ligand 1 immune checkpoint blockade promoted immune evasion by epigenetic Tap1 (transporter associated with antigen processing 1) silencing, increasing selection of metastatic tumor variants with defective interferon-gamma (IFN-gamma)-inducible class I major histocompatibility complex (MHC-I) expression. Unleashing CD4 conventional T cells by regulatory T cell (T(reg) cell) depletion, transfer of tumor-reactive CD4 T cells, or anti-CTLA-4 prevented metastasis. Tumor-specific CD4 T cells adopted a TCF-1(+)SLAMF6(+) progenitor state in lymph nodes and differentiated in tumors. Anti-CTLA-4 increased intratumoral accumulation of CD4 T cells with stemness and tissue residency features, reduced metastasis, and induced gene signatures correlated with improved patient outcomes. MHC-I restoration with anti-CTLA-4 prolonged survival in murine models. In patient tumors, T(reg) cells and CD4 T cells colocalized, and abundance correlated with survival. These findings identify targetable mechanisms of immune evasion and metastasis in immunotherapy-resistant cancer. |
