Regulation of inhibitory DAMP to harness immunogenic cell death

项目摘要 大多数抗癌疗法将细胞死亡指定为最终目标。然而，细胞之外的迷人生物学 死亡正在成为治疗结果的一个重要因素。一个临床相关的例子是 免疫原性细胞死亡（ICD）-其特征在于其增强抗肿瘤T细胞免疫的功能能力。 目前定义ICD的分子标志是释放损伤相关分子模式（DAMP）， 其作为“危险”信号起作用以最终激活T细胞免疫。然而，我们的初步发现 结果显示，单靠成功的DAMP释放不足以促进ICD的发展，这使我们对这一点提出了挑战。 除了DAMP之外的其他调节组分影响免疫原性的教条和理由 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DAMP（iDAMP）， 作为对化疗的生理反应，死亡细胞同时释放调节机制 治疗有趣的是，阻止死亡细胞释放iDAMP的药物干预减轻了细胞凋亡。 iDAMP施加的免疫抑制限制，并且容易实现非免疫原性化疗 引发抗肿瘤T细胞反应。我们现在建议阐明1）未探索的上游调控 iDAMP的机制和2）iDAMP阻断作为增加抗肿瘤T细胞的可推广策略 免疫力我们的基本假设是，iDAMP轴的药物干预构成了一个新的机制。 范式转变的方法，以增加抗肿瘤T细胞免疫和治疗效果。获得的知识 从拟议的研究将阐明上皮癌细胞的上游机制， iDAMP生物合成和释放作为对抗癌治疗生理反应，以及评估 可以减轻iDAMP的免疫抑制限制以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一个令人信服的科学理由， 通过将我们的临床前研究成果转化为临床应用，

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.