T reg cells promote immunotherapy-induced immune evasion by restraining CD4 T cell control of MHC-I–deficient metastatic pancreatic cancer

Abstract

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-γ (IFN-γ)–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. MHC-I–defective metastatic cancer after immunotherapy can be overcome by harnessing antitumor CD4 T cells. Metastasis of pancreatic ductal adenocarcinoma (PDA) after immunotherapy is driven by immune evasion. Using murine PDA models, Schmiechen et al. determined that PD-L1 blockade caused epigenetic silencing of Tap1 , a peptide transporter essential for interferon-γ (IFN-γ)–induced class I major histocompatibility complex (MHC-I) expression, increasing the survival of tumor escape variants. Regulatory T cells prevented CD4 conventional T cells (T conv cells) from eliminating tumor escape variants with defective MHC-I expression, which promoted immune evasion and metastasis. Pharmacological restoration of IFN-γ–inducible MHC-I expression and CTLA-4 blockade enhanced an intratumoral CD4 T conv cell state with features of antigen recognition, tissue residency, and stemness, revealing effective strategies against metastasis in PDA. —Leoma Bere