TY - JOUR
T1 - Bcell-derived IL35 drives STAT3-DependentCD8+ T-cell exclusion in pancreatic cancer
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
N1 - Funding Information:
We thank B. Savoldo and G. Dotti for discussions and help with manuscript preparation. This work was supported in part by R37 CA230786 (Y. Pylayeva-Gupta), University Cancer Research Fund at The University of North Carolina (UNC) at Chapel Hill (Y. Pylayeva-Gupta); AACR–PanCAN Pathway to Leadership Grant 13-70-25-PYLA (Y. Pylayeva-Gupta), V Foundation for Cancer Research grant V2016-016 (Y. Pylayeva-Gupta), Concern Foundation Conquer Cancer Now Award (Y. Pylayeva-Gupta), the Washington University in St. Louis SPORE in Pancreatic Cancer (R.C. Fields and W.G. Hawkins; P50CA196510), the WUSTL SPORE Career Enhancement Award grant 1P50CA196510-01A1 from the NCI (Y. Pylayeva-Gupta), Cancer Cell Biology Training Program (CCBTP) grant 2T32CA071341-21 (D. Michaud), and R01 CA203689 (D.A.A. Vignali). The UNC Flow Cytometry Core Facility, the UNC Translational Pathology Laboratory, the Animal Histopathology and Laboratory Medicine Core, and the UNC Lineberger Animal Studies Core are supported in part by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85081126174&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-19-0349
DO - 10.1158/2326-6066.CIR-19-0349
M3 - Article
C2 - 32024640
AN - SCOPUS:85081126174
SN - 2326-6066
VL - 8
SP - 292
EP - 308
JO - Cancer immunology research
JF - Cancer immunology research
IS - 3
ER -