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

项目摘要 慢性感染和癌症与抑制T细胞反应有关，导致无法控制 这些疾病。在过去的15年里，阻断负免疫调节剂在小范围内被证明是有效的 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。尽管如此 令人鼓舞的结果是，目前还没有针对慢性病毒感染的有效免疫疗法，大多数患者未能 对检查站封锁作出反应或产生抵抗。最近的研究发现了类似记忆的CXCR5+TCF1+CD8+ 在持续感染和癌症期间维持T细胞反应的T细胞。重要的是，这些细胞产生 在抗PD1治疗后观察到的主要增殖性猝发。此外，TCF1+CD8T细胞数量 与抗PD-1治疗的良好反应有关。因此，扩大这些细胞的方法 都在积极寻找。 我们最近报道，阻断干扰素-I受体会导致CXCR5+的扩张 CD8+T细胞以IL-27依赖的方式表达。IFNAR1阻断促进细胞加速分裂和保留 在病毒特异性耗尽的CD8+T细胞中表达TCF1。我们发现CD8+T细胞固有的IL-27信号促进 高TCF1的细胞维持增殖并避免细胞程序性死亡。从机制上讲，IL-27被赋予 使用IRF1快速分裂细胞，IRF1是细胞内持续分裂所必需的转录因子 举止。这些发现表明IL-27对TCF1+CD8 T细胞的扩增是必不可少的。 持续的病毒感染。我们假设由特定细胞亚群产生的IL-27对 保护快速潜水的CD8 T细胞在持续病毒感染和 癌症。我们建议在这一应用中探索IL-27信号的基本生物学，因为它与CD8 T细胞有关 扩张、生存和功能。我们将评估诱导IL-27的细胞群体和信号 生产，评估IL-27如何阻止快速潜水的TCF1+CD8 T细胞的凋亡，并扩大我们的探索 在LCMV持续感染和同基因感染期间，抗PD-1/L1治疗后的IL-27信号是否 肿瘤对CD8T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 基本了解IL-27如何调节抗病毒和抗肿瘤反应。此外，这项研究的发现 应该指出可以用来维持最佳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.