| First Author | Mirlekar B | Year | 2020 |
| Journal | Cancer Immunol Res | Volume | 8 |
| Issue | 3 | Pages | 292-308 |
| PubMed ID | 32024640 | Mgi Jnum | J:298364 |
| Mgi Id | MGI:6472196 | Doi | 10.1158/2326-6066.CIR-19-0349 |
| Citation | Mirlekar B, et al. (2020) B cell-Derived IL35 Drives STAT3-Dependent CD8(+) T-cell Exclusion in Pancreatic Cancer. Cancer Immunol Res 8(3):292-308 |
| abstractText | 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 IFNgamma 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. |
