Targeting Regulatory T cells controls metastatic pancreatic ductal adenocarcinoma by modulation of conventional CD4 T helper cells 3557

Abstract Description Pancreatic ductal adenocarcinoma (PDA) has a dismal 5-year survival rate of 12 percent. Lethality is attributed to late diagnosis, early metastasis, and therapeutic resistance. We identified pancreatic tumor cells derived from mice which resist immunotherapy (e.g., escape variants, EV) rapidly metastasize after orthotopic implantation into syngeneic immunocompetent mice. A defect in IFN-inducible Tap1 and MHC class I render EVs resistant to CD8 T cell-mediated control of tumor growth in vivo. EV metastases were enriched for CD4+ Foxp3+ Tregs. Treg depletion interfered with primary EV growth, prevented metastasis and improved tumor-specific T cell function independent of CD8 T cells and NK cells. However, loss of conventional Foxp3- CD4 T cells (CD4 Th) resulted in fulminant metastases despite Treg depletion. Thus, CD4 Th engagement is critical to interfere with metastasis that lost MHC class I. Anti-CTLA4 specifically decreased intratumoral Tregs and expanded PD1+Slamf6+Cxcr6+ CD4 Th cells. While restoring MHC class I or anti-CTLA4 resulted in modest prolongation of mouse survival, the combination synergized to slow tumor growth and interfere with metastases resulting in a doubling of survival and 4/10 mice cured. Tumor-specific tissue resident memory CD4 and CD8 T cells expressing CD49a and CD69 were enriched in the pancreas and dLN of cured animals. Together, our results support that immunotherapy modulating CD4 T cells improves control of PDA metastases. Funding Sources ZCS is supported by a NIH T32 AG029796 followed by NIH F31CA275289. IMS is supported by NIH R01CA255039, R01CA249393, U54CA268069, P01CA254849, DOD W81XWH2110525, an AACR Pancreatic Cancer Action Network Catalyst Award (19-35- STRO), American Cancer Society RSG-21-102-01-IBCD, and Randy Shaver Research grant. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)