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.

中文翻译：

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B 细胞衍生的 IL35 驱动胰腺癌中 STAT3 依赖性 CD8+ T 细胞排斥。


胰腺导管腺癌 (PDA) 是一种侵袭性恶性肿瘤，其特征是肿瘤近端 CD8+ T 细胞缺乏且对免疫治疗干预具有抵抗力。引发 CD8+ T 细胞排斥和免疫治疗耐药的癌症相关机制尚不清楚。在这里，使用 Kras 和 p53 驱动的 PDA 模型，我们描述了促肿瘤细胞因子 IL35 通过 STAT3 激活 CD8+ T 细胞的作用机制。与对 CD4+ T 细胞的作用不同，gp130+CD8+ T 细胞中的 IL35 信号传导激活转录因子 STAT3，通过抑制 CXCR3、CCR5 和 IFNγ 表达来拮抗 CD8+ T 细胞的瘤内浸润和效应功能。抑制肿瘤诱导的 CD8+ T 细胞中的 STAT3 信号传导可改善过继转移至荷瘤小鼠后的 PDA 生长控制。我们发现 CD8+ T 细胞中 STAT3 的激活是由 B 细胞而非调节性 T 细胞特异性产生 IL35 驱动的。我们还证明，B 细胞特异性删除 IL35 可独立于效应细胞或调节性 CD4+ T 细胞促进 CD8+ T 细胞激活，并且足以表型复制治疗性抗 IL35 阻断以克服抗 PD-1 免疫疗法的耐药性。最后，我们在 PDA 患者中鉴定了循环 IL35+ B 细胞亚群，并证明 IL35+ 细胞的存在预示着肿瘤中磷酸化 (p)Stat3+CXCR3-CD8+ T 细胞的出现增加，并与细胞毒性 T 细胞特征呈负相关在患者中。总之，这些数据表明 B 细胞介导的 IL35/gp130/STAT3 信号传导与 PDA 中 CD8+ T 细胞排斥和免疫治疗耐药性具有重要的直接联系。