PT  - JOURNAL ARTICLE
AU  - Mirlekar, Bhalchandra
AU  - Michaud, Daniel
AU  - Lee, Samuel J.
AU  - Kren, Nancy P.
AU  - Harris, Cameron
AU  - Greene, Kevin
AU  - Goldman, Emily C.
AU  - Gupta, Gaorav P.
AU  - Fields, Ryan C.
AU  - Hawkins, William G.
AU  - DeNardo, David G.
AU  - Rashid, Naim U.
AU  - Yeh, Jen Jen
AU  - McRee, Autumn J.
AU  - Vincent, Benjamin G.
AU  - Vignali, Dario A.A.
AU  - Pylayeva-Gupta, Yuliya
TI  - B cell–Derived IL35 Drives STAT3-Dependent CD8<sup>+</sup> T-cell Exclusion in Pancreatic Cancer
AID  - 10.1158/2326-6066.CIR-19-0349
DP  - 2020 Mar 01
TA  - Cancer Immunology Research
PG  - 292--308
VI  - 8
IP  - 3
4099  - http://cancerimmunolres.aacrjournals.org/content/8/3/292.short
4100  - http://cancerimmunolres.aacrjournals.org/content/8/3/292.full
SO  - Cancer Immunol Res2020 Mar 01; 8
AB  - 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.