DOI: 10.1126/sciimmunol.adz4302 ISSN: 2470-9468
T
reg
cells promote immunotherapy-induced immune evasion by restraining CD4 T cell control of MHC-I–deficient metastatic pancreatic cancer
Zoe C. Schmiechen, Eduardo Cruz-Hinojoza, Audrey L. Hilk, Madeline A. Ellefson, Alexander K. Tsai, Olivia M. Dres, Liang-I Kang, Michael J. Geuenich, Jonah Z. Butler, Adam L. Burrack, Brandon M. Larsen, Grant H. Hickok, Ebony A. Miller, Cara-lin Lonetree, Amrit Gaire, Rachana Pandey, Hezkiel A. Nanda, Indrajit Chaudhury, Thomas Corbiere, Thamotharampillai Dileepan, Steven S. Shen, Kieran R. Campbell, David G. DeNardo, Ingunn M. Stromnes
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.