Abstract I04: Regulatory T-cell depletion causes compensatory immune suppression and accelerates pancreatic carcinogenesis

In human patients and in mouse models, immunosuppressive regulatory T cells (Tregs) accumulate in pancreatic cancer. Tregs are considered a potential therapeutic target with the goal to reverse immunosuppression in a number of malignancies, including pancreatic cancer. Using a genetically engineered mouse model of pancreatic cancer, we determined that—unlike in other malignancies—Treg depletion failed to relieve immunosuppression. Contradicting the current paradigm, depletion of Tregs led to accelerated tumor progression. We show that Tregs are a key source of TGFb ligands both in human samples and in mouse models. Accordingly, their depletion reprograms the fibroblast population, exemplified by loss of smooth muscle actin expression and an increase in the myeloid-recruiting chemokines Ccl3, Ccl6, and Ccl8. Our findings point to a dual role of Tregs in pancreatic cancer, with their immune-suppressive function being balanced by their induction of a SMA-high (tumor-restraining) fibroblast phenotype. Further, our data point to a compensatory immunosuppression mechanism that confers resistance to Treg depletion in pancreatic cancer. Finally, blockade of the common CCL3/6/8 receptor CCR1 combined with Treg-depletion successfully inhibited tumorigenesis, a finding with potential therapeutic implications. Citation Format: Yaqing Zhang, Jenny Lazarus, Nina Steele, Ho-Joon Lee, Wei Yan, Cristopher J. Halbrook, Rosa Menjivar, Samantha B. Kemp, Veerin Sirihoracai, Eileen S. Carpenter, Anna C. Nevison, Alekya Vinta, Michelle A. Anderson, Howard C. Crawford, Costas A. Lyssiotis, Timothy L. Frankel, Filip Bednar, Marina Pasca di Magliano. Regulatory T-cell depletion causes compensatory immune suppression and accelerates pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I04.