Abstract B45: IL35/STAT3 axis as regulator of tolerance and T-cell exclusion in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy refractory to immunotherapeutic interventions. The mechanisms that drive robust immunosuppression and CD8+ T-cell dysfunction in PDA are not well known. Using the Kras- and p53-driven mouse model of pancreatic cancer, we show that activation of IL35/STAT3 pathways directs reprogramming of suppressive regulatory B-cell lineage and inhibits CD8+ T cells via suppression of gene program that regulates infiltration and effector function. Activation of STAT3 in CD8+ T cells is driven by B cell, but not Treg-specific production of cytokine IL35. Targeting IL35 via cell lineage-specific deletion or therapeutic anti-IL35 blockade converts PDA from CD8+ T cell low to high tumor and confers sensitivity to anti-PD1 immunotherapy. Therapeutic inhibition of STAT signaling in tumor-educated CD8+ T cells improves PDA growth control upon adoptive transfer to tumor-bearing animals. Finally, we identify IL35+ B cell subset in patients with PDA and demonstrate that the presence of IL35+ cells in tumor samples predicts increased occurrence of dysfunctional CD8+ T cells. Together, these data identify IL35/STAT3 signaling as an important mediator of immune tolerance and a direct link to CD8+ T-cell exclusion and immunotherapy resistance in PDA. Citation Format: Bhalchandra Mirlekar, Daniel Michaud, Yuliya Pylayeva-Gupta. IL35/STAT3 axis as regulator of tolerance and T-cell exclusion in pancreatic cancer [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 B45.