Mirlekar et al. found that in the context of pancreatic ductal adenocarcinoma (PDA), IL-35 is produced primarily by Bregs and CD4+ T cells (both FoxP3+ and FoxP3-). In mice lacking IL-35, PDA tumor growth was reduced, infiltration by activated cytotoxic CD8+ T cells and effector CD4+ T cells (including those expressing IFNγ and TNFα) was increased, and Treg frequency was decreased. While PDA is typically resistant to anti-PD-1 immunotherapy, mice lacking IL-35 responded to anti-PD-1 (accompanied by enhanced CD8+ T cell infiltration), suggesting that targeting IL-35 could help overcome resistance to immunotherapy in PDA.

Although successes in cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic ductal adenocarcinoma (PDA). Mechanisms that contribute to the poor antitumor immune response in PDA are not well understood. Here, we demonstrated that cytokine IL35 is a major immunosuppressive driver in PDA and potentiates tumor growth via the suppression of endogenous antitumor T-cell responses. The growth of pancreatic tumors in mice deficient for IL35 was significantly reduced. An analysis of tumor-infiltrating immune cells revealed a role for IL35 in the expansion of regulatory T cells and the suppression of CD4+ effector T cells. We also detected a robust increase in both the infiltration and activation of cytotoxic CD8+ T cells, suggesting that targeting IL35 may be an effective strategy to convert PDA from an immunologically 'cold' to 'hot' tumor. Although PDA is typically resistant to anti-PD-1 immunotherapy, we demonstrated robust synergistic reduction in tumor growth when IL35 deficiency was combined with anti-PD-1 treatment. These findings provide new insight into the function of IL35 in the pathogenesis of pancreatic cancer and underscore the potential significance of IL35 as a therapeutic target for use in combination immunotherapy approaches in this deadly malignancy.

Author Info: (1) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. (2) Cell Biology and Physiology, University of North Carolina at Chapel Hill. (3)

Author Info: (1) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. (2) Cell Biology and Physiology, University of North Carolina at Chapel Hill. (3) Genetics, University of North Carolina at Chapel Hill. (4) Pathology and Lab Medicine, University of North Carolina at Chapel Hill. (5) Genetics, University of North Carolina at Chapel Hill yuliyap1@email.unc.edu.

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