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，阻断负性免疫调节因子已被证明在小范围内有效。 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，没有有效的免疫疗法存在慢性病毒感染，大多数患者未能 对检查站封锁作出反应或产生抵抗。最近的工作确定了记忆样CXCR 5 + TCF 1 + CD 8 + 在持续感染和癌症期间维持T细胞应答的T细胞。重要的是，这些细胞产生 抗PD 1治疗后观察到的主要增殖爆发。此外，TCF 1 + CD 8 T细胞的数量 与抗PD-1治疗的有利反应相关。因此，扩增这些细胞的方法 积极寻求。 我们最近报道，阻断干扰素1型（IFN-I）受体导致CXCR 5+细胞扩增， CD 8 + T细胞以IL-27依赖性方式表达。IFNAR 1阻断促进加速细胞分裂和保留 TCF 1在病毒特异性耗尽的CD 8 + T细胞中的表达。我们发现，CD 8 + T细胞内在IL-27信号转导促进 TCF 1-高细胞维持增殖并避免程序性细胞死亡。从机制上讲，IL-27赋予了 快速分裂的细胞与IRF 1，一种转录因子，需要在细胞内持续分裂， 方式这些发现揭示了IL-27对于TCF 1 + CD 8 T细胞的扩增是必需的， 持续性病毒感染我们假设特定细胞亚群产生的IL-27是 在持续性病毒感染期间， 癌在本申请中，我们提出探索IL-27信号传导的基础生物学，因为它涉及CD 8 T细胞 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如何防止快速潜水TCF 1 + CD 8 T细胞凋亡，并扩大我们的探索 在持续性LCMV感染和同源性LCMV感染期间，抗PD-1/L1治疗后IL-27信号传导是否 在肿瘤中，CD 8 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 了解IL-27如何调节抗病毒和抗肿瘤反应。此外，这项研究的结果 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.