Abstract A033: Blocking TNF-a producing macrophage activates antitumor immunity in pancreatic cancer via IL33

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) remains resistant to immune therapies, largely due to robustly fibrotic and immunosuppressive tumor microenvironments. It has been postulated that excessive accumulation of immunosuppressive myeloid cells influences immunotherapy resistance and recent studies targeting macrophages in combination with checkpoint blockade have demonstrated promising preclinical results. Yet, our understanding of tumor-associated macrophage (TAM) function, complexity, and diversity in PDA remains limited. Here, analysis of human PDA single cell sequencing data revealed significant macrophage heterogeneity, with bone marrow-derived monocytes serving as the primary source for immunosuppressive TAMs. These bone marrow derived macrophages also served as a primary source of TNF-a. Deletion of Ccr2 in genetically engineered KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) mice decreased monocyte recruitment resulting in decreased metastasis, and increased survival. Moreover, intervention studies targeting CCR2 with a new orthosteric inhibitor (CCX598) renders PDA susceptible to checkpoint blockade therapy (CTLA-4 and PD-L1) resulting in reduced metastatic burden and increased survival in KPC mice. Additionally, TNF-a suppresses the expression of alarmin IL-33 in cancer cells, thereby hindering dendritic cell and cytotoxic T cell anti-tumor activity. When put together our data indicate that interventions to disrupt infiltration of immunosuppressive macrophages lead to decreased TNF-a, decreased metastasis and increased survival in two different models suggesting its potential role to overcome barriers to effective immunotherapeutics for PDA. Citation Format: Ajay Dixit, Paolo Provenzano, Aaron Sarver, Jon Zettervall, Huocong Huang, Kexin Zheng, Rolf Brekken. Blocking TNF-a producing macrophage activates antitumor immunity in pancreatic cancer via IL33 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A033.