TCR signaling and cell cycle regulation in tumor-specific CD8 T cell dysfunction

项目摘要 T细胞具有识别和消除癌细胞的潜力。然而，尽管如此，癌症通常会进展 肿瘤内的肿瘤特异性T细胞。虽然目前的免疫疗法，如免疫检查点， 阻断可以在某些癌症类型的患者中带来持久的缓解，大多数患者 没有治愈。使用遗传性肝癌小鼠模型，我们先前证明了肿瘤特异性T细胞， 进入恶性肝脏后，迅速分化为早期和晚期功能障碍状态，由 不同的表观遗传程序晚期功能失调的肿瘤特异性T细胞在移植后未能再次发挥功能。 免疫检查点阻断的反应，我们发现，从患者的人肿瘤浸润淋巴细胞， 与我们的小鼠肝癌中晚期功能障碍T细胞的关键表观遗传特征相同， 模型因此，癌症免疫治疗的关键挑战是如何防止或逆转肿瘤特异性T细胞 进入这种后天强迫的功能失调状态我们现在发现，晚期TST未能增殖， 对T细胞受体刺激的反应，我们假设晚期功能性拯救的屏障 功能障碍的肿瘤特异性T细胞是它们不能响应TCR刺激而进入细胞周期。我们将 利用我们的临床前小鼠癌症模型，研究人类患者肝脏和乳腺肿瘤中的TIL， (i)了解细胞周期动力学和T细胞受体信号转导缺陷在功能障碍期间如何变化 分化，（ii）定义细胞周期和表观遗传变化如何决定功能拯救，以及（iii）测试 克服晚期功能障碍性T细胞中的细胞周期和TCR信号传导缺陷的策略。这些研究将 揭示细胞周期和T细胞受体信号传导如何调节T细胞表观基因组的关键见解，并测试 克服肿瘤特异性T细胞重编程障碍的治疗适用策略， 从而改善癌症免疫疗法。

PROJECT SUMMARY T cells have the potential to recognize and eliminate cancer cells. However, most often cancers progress in spite of the tumor-specific T cells present within tumors. While current immunotherapies such as immune checkpoint blockade can bring about long-lasting remissions in some patients with certain cancer types, most patients are not cured. Using a genetic liver cancer mouse model, we previously demonstrated that tumor-specific T cells, after entering malignant livers, rapidly differentiate to an early and then late dysfunctional state, encoded by distinct epigenetic programs. Late dysfunctional tumor-specific T cells failed to become functional again in response to immune checkpoint blockade, and we found that human tumor-infiltrating lymphocytes from patients with solid tumors shared key epigenetic hallmarks of late dysfunctional T cells from our mouse liver cancer model. Thus, a critical challenge for cancer immunotherapy is how to prevent or revert tumor-specific T cells from entering this epigenetically-enforced dysfunctional state. We now find that late TST fail to proliferate in response to T cell receptor stimulation, and we hypothesize that the barrier to functional rescue of late dysfunctional tumor-specific T cells is their inability to enter cell cycle in response to TCR stimulation. We will leverage our preclinical mouse cancer models and study TIL in liver and breast tumors from human patients to (i) understand how cell cycle kinetics and T cell receptor signaling defects change during dysfunctional differentiation, (ii) define how cell cycle and epigenetic changes determine functional rescue, and (iii) test strategies to overcome cell cycle and TCR signaling defects in late dysfunctional T cells. These studies will uncover critical insights into how cell cycle and T cell receptor signaling regulate the T cell epigenome and test therapeutically-applicable strategies to overcome barriers to tumor-specific T cell reprogramming, which may lead to improved cancer immunotherapies.