Bcell-derived IL35 drives STAT3-DependentCD8+ T-cell exclusion in pancreatic cancer

Bhalchandra Mirlekar, Daniel Michaud, Samuel J. Lee, Nancy P. Kren, Cameron Harris, Kevin Greene, Emily C. Goldman, Gaorav P. Gupta, Ryan C. Fields, William G. Hawkins, David G. DeNardo, Naim U. Rashid, Jen Jen Yeh, Autumn J. McRee, Benjamin G. Vincent, Dario A.A. Vignali, Yuliya Pylayeva-Gupta

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by a paucity of tumor-proximal CD8+ T cells and resistance to immunotherapeutic interventions. Cancer- associated mechanisms that elicit CD8+ T-cell exclusion and resistance to immunotherapy are not well-known. Here, using a Kras- and p53-driven model of PDA, we describe a mechanism of action for the protumorigenic cytokine IL35 through STAT3 activation in CD8+ T cells. Distinct from its action on CD4+ T cells, IL35 signaling in gp130+CD8+ T cells activated the transcription factor STAT3, which antagonized intratumoral infiltration and effector function of CD8+ T cells via suppression of CXCR3, CCR5, and IFNγ expression. Inhibition of STAT3 signaling in tumor-educated CD8+ T cells improved PDA growth control upon adoptive transfer to tumor-bearing mice. We showed that activation of STAT3 in CD8+ T cells was driven by B cell- but not regulatory T cell-specific production of IL35. We also demonstrated that B cell-specific deletion of IL35 facilitated CD8+ T-cell activation independently of effector or regulatory CD4+ T cells and was sufficient to phenocopy therapeutic anti-IL35 blockade in overcoming resistance to anti-PD- 1 immunotherapy. Finally, we identified a circulating IL35+ B-cell subset in patients with PDA and demonstrated that the presence of IL35+ cells predicted increased occurrence of phosphorylated (p)Stat3+CXCR3-CD8+ T cells in tumors and inversely correlated with a cytotoxic T-cell signature in patients. Together, these data identified B cell-mediated IL35/gp130/STAT3 signaling as an important direct link to CD8+ T-cell exclusion and immunotherapy resistance in PDA.

Original languageEnglish
Pages (from-to)292-308
Number of pages17
JournalCancer immunology research
Volume8
Issue number3
DOIs
StatePublished - Mar 1 2020

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    Mirlekar, B., Michaud, D., Lee, S. J., Kren, N. P., Harris, C., Greene, K., Goldman, E. C., Gupta, G. P., Fields, R. C., Hawkins, W. G., DeNardo, D. G., Rashid, N. U., Yeh, J. J., McRee, A. J., Vincent, B. G., Vignali, D. A. A., & Pylayeva-Gupta, Y. (2020). Bcell-derived IL35 drives STAT3-DependentCD8+ T-cell exclusion in pancreatic cancer. Cancer immunology research, 8(3), 292-308. https://doi.org/10.1158/2326-6066.CIR-19-0349