Regulation of inhibitory DAMP to harness immunogenic cell death

项目总结 大多数抗癌疗法都将细胞死亡作为最终目标。然而，细胞之外令人着迷的生物学 死亡正在成为治疗结果的重要贡献者。一个与临床相关的例子是 免疫原性细胞死亡(ICD)--以增强抗肿瘤T细胞免疫的功能为特征。 ICD目前定义的分子特征是损伤相关分子模式(DAMP)的释放， 它们的作用是最终激活T细胞免疫的“危险”信号。然而，我们的初步调查结果 揭示了仅成功释放湿气不足以推广ICD；这导致我们对此提出挑战 附加调节成分(S)影响免疫原性的教义和理由 细胞死亡。在此，我们的新发现还揭示了一种上游不清楚的抑制性阻滞剂(IDAMP) 作为对化疗的生理反应，死亡细胞同时释放了调节机制。 治疗。有趣的是，阻止濒死细胞释放iDAMP的药物干预缓解了 IDAMP施加的免疫抑制限制，并容易实现非免疫原性化疗 以诱导抗肿瘤T细胞反应。我们现在建议澄清1)未探索的上游监管 IDAMP的机制(S)和2)iDAMP阻断作为增强抗肿瘤T细胞的通用策略 豁免权。我们的基本假设是，对iDAMP轴的药物干预表现为 范式转换方法增强抗肿瘤T细胞免疫和治疗效果。获得的知识 将阐明调控上皮性癌细胞的上游机制 IDAMP的生物合成和释放作为抗癌治疗的生理反应，以及评估 可以缓解免疫抑制的iDAMP增强抗肿瘤作用的治疗方法 T细胞免疫。拟议研究的成功将产生令人信服的科学理由，以推动 通过将我们的临床前研究成果转化为临床应用，推动领域向前发展。

PROJECT SUMMARY Most anti-cancer therapies designate cell death as the ultimate end goal. Yet, the fascinating biology beyond cell death is emerging as an important contributor to therapeutic outcome. A clinically-relevant example is immunogenic cell death (ICD)—characterized by its functional capacity to potentiate antitumoral T cell immunity. The current defining molecular hallmark of ICD is the release of damage-associated molecular patterns (DAMPs), which function as “danger” signals to ultimately activate T cell immunity. However, our preliminary findings revealed that successful DAMP release alone was insufficient to promote ICD; leading us to challenge this dogma and reason that additional regulatory component(s), other than DAMPs, influence the immunogenicity of cell death. Herein, our new findings also revealed that an inhibitory DAMP (iDAMP) with unclear upstream regulatory mechanisms was concurrently released by dying cells as a physiologic response to chemotherapeutic treatment. Intriguingly, the pharmacological intervention to preclude iDAMP release by dying cells relieved the immunosuppressive constraints imposed by the iDAMP, and readily enabled a non-immunogenic chemotherapy to elicit an antitumoral T cell response. We now propose to elucidate 1) the unexplored upstream regulatory mechanism(s) of the iDAMP and 2) iDAMP blockade as a generalizable strategy to augment antitumoral T cell immunity. Our underlying hypothesis is that pharmacological intervention of the iDAMP axis poses as a paradigm-shifting approach to augment antitumoral T cell immunity and therapeutic efficacy. Knowledge gained from the proposed research will elucidate the upstream mechanism in epithelial cancer cells that regulates iDAMP biosynthesis and release as a physiologic response to anti-cancer therapy, as well as evaluate a therapeutic approach that can alleviate the immunosuppressive constraints of the iDAMP to augment antitumoral T cell immunity. The success of the proposed research will yield a compelling scientific rationale to move the field forward by translating our preclinical findings into clinical application.