The role of IL-27 in sustaining the exhausted CD8 T cell response to persistent infection and cancer.

项目概要 慢性感染和癌症与 T 细胞反应受抑制有关，导致无法控制 这些疾病。在过去 15 年里，事实证明，阻断负性免疫调节因子在一小部分患者中是有效的。 癌症患者的数量，并在慢性病毒感染的动物模型中显示出希望。尽管有这些 令人鼓舞的结果是，对于慢性病毒感染尚无有效的免疫疗法，而且大多数患者未能 对检查站封锁做出反应或产生抵抗力。最近的工作确定了类似记忆的 CXCR5 TCF1 CD8 T 细胞在持续感染和癌症期间维持 T 细胞反应。重要的是，这些细胞产生 抗 PD1 治疗后观察到的主要增殖爆发。此外，TCF1 CD8 T细胞的数量 肿瘤中的活性与抗 PD-1 治疗的良好反应相关。因此，扩展这些细胞的方法 正在积极寻找。 我们最近报道，阻断 1 型干扰素 (IFN-I) 受体会导致 CXCR5 扩增 CD8 T 细胞以 IL-27 依赖性方式。 IFNAR1阻断促进加速细胞分裂和保留 病毒特异性耗尽的 CD8 T 细胞中的 TCF1。我们发现 CD8 T 细胞固有的 IL-27 信号传导促进 TCF1高细胞维持增殖并避免程序性细胞死亡。从机制上讲，IL-27 赋予 具有 IRF1 的快速分裂细胞，IRF1 是细胞固有的持续分裂所需的转录因子 方式。这些发现表明，IL-27 对于 TCF1 CD8 T 细胞的扩增至关重要 持续的病毒感染。我们假设特定细胞亚群产生的 IL-27 对于 保护快速潜水的 CD8 T 细胞在持续病毒感染和 癌症。我们建议在此申请中探索 IL-27 信号传导的基本生物学，因为它与 CD8 T 细胞相关 扩展、生存和功能。我们将评估诱导 IL-27 的细胞群和信号 生产，评估 IL-27 如何防止快速潜水的 TCF1 CD8 T 细胞凋亡并扩大我们的探索 研究持续性 LCMV 感染和同基因期间抗 PD-1/L1 治疗后 IL-27 信号传导是否存在 肿瘤对于 CD8 T 细胞的扩增/功能至关重要。一旦完成，这些研究将提供重要的 IL-27 如何调节抗病毒和抗肿瘤反应的基本知识。此外，这项研究的结果 应该指出可用于维持最佳 T 细胞反应的治疗方法和方式。

Project Summary Chronic infection and cancer are associated with suppressed T cell responses resulting in the inability to control these diseases. Over the last 15 years, blockade of negative immune regulators has proven effective in a small number of cancer patients and shown promise in animal models of chronic viral infection. Despite these encouraging results, no effective immune therapies exist for chronic viral infection and most patients fail to respond or develop resistance to checkpoint blockade. Recent work identified memory-like CXCR5+ TCF1+ CD8+ T cells which sustain T cell responses during persistent infection and cancer. Importantly, these cells generate the major proliferative burst observed following anti-PD1 treatment. Further, the numbers of TCF1+ CD8 T cells in tumors correlate with favorable responses to anti-PD-1 treatment. As such, approaches to expand these cells are actively sought. We recently reported that blockade of interferon type 1 (IFN-I) receptor leads to expansion of CXCR5+ CD8+ T cells in an IL-27-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific exhausted CD8+ T cells. We found that CD8+ T cell-intrinsic IL-27 signaling promotes the TCF1-high cells to maintain proliferation and avoid programmed cell death. Mechanistically, IL-27 endowed rapidly dividing cells with IRF1, a transcription factor that was required for sustained division in a cell-intrinsic manner. These findings revealed that IL-27 is essential for the expansion of TCF1+ CD8 T cells following persistent viral infection. We hypothesize that IL-27 produced by specific cell subsets is necessary to safeguard rapidly diving CD8 T cells from apoptotic cell death during both persistent viral infection and cancer. We propose in this application to explore the basic biology of IL-27 signaling as it relates to CD8 T cell expansion, survival and function. We will assess the cellular populations and signals that induce IL-27 production, assess how IL-27 prevents apoptosis of rapidly diving TCF1+ CD8 T cells and expand our exploration into whether IL-27 signaling following anti-PD-1/L1 treatment during persistent LCMV infection and syngeneic tumors is crucial for the CD8 T cell expansion/function. Once completed these studies will provide important basic knowledge of how IL-27 regulates anti-viral and anti-tumor responses. Moreover, findings from this study should point the way to treatments and modalities that can be employed to sustain optimal T cells responses.