Enhancing Ferroptosis to Augment Responses to Immune Checkpoint Blockade

摘要： 非小细胞肺癌、结直肠癌、肾细胞癌和黑色素瘤占五种癌症中的四种 退伍军人中最常见的癌症形式。在转移性环境中，免疫疗法已成为一种 强大的肿瘤治疗方式能够对所有这些疾病产生持久的控制。 不幸的是，绝大多数退伍军人并没有从这种疗法中受益，因此，我们的长期目标是 制定与放射治疗相结合的综合治疗策略，以增强免疫治疗的疗效。的 该提案的总体目标是确定放射治疗诱导的细胞死亡的重要性 免疫治疗疗效。该提案的中心假设是增强免疫刺激 辐射诱导的铁死亡将增强免疫治疗的疗效。该提案的理由来自于 我们已发表和未发表的数据表明，放疗会诱发肿瘤铁死亡， 观察到放疗和免疫疗法协同作用，通过铁死亡促进肿瘤控制。 除此之外，我们的结果表明铁死亡可能是细胞死亡的一种免疫原性形式。这个假设 将在治疗上进行评估和利用，以设计合理的放射治疗组合策略 和免疫疗法的三个目标。目标 1 将定义分子介质（目标 1A-C）和信号传导途径 （目标 1D）辐射诱导的脂质氧化和铁死亡调节抗肿瘤免疫。目标2将 确定辐射诱导脂质的先天性（目标 2A、B）和适应性（目标 2C）细胞介质 氧化和铁死亡调节抗肿瘤免疫。目标 3 将制定治疗策略 调节放疗引起的铁死亡以系统性增强免疫检查点阻断功效 原发性 (Aim 3A) 和转移性 (Aim 3B) 黑色素瘤模型中的（远隔反应）。此外，我们 将开发功效的药效生物标志物（目标3C）。所提出的研究具有创新性，因为 铁死亡的免疫原性尚未得到表征。这些目标的完成意义重大 因为它将在铁死亡、细胞毒性肿瘤治疗方式之间建立一种新的机制联系， 和免疫极化，可以在治疗上利用它来提高免疫治疗的功效 退伍军人。

Abstract: Non-small cell lung cancer, colorectal cancer, renal cell carcinoma, and melanoma represent four of the five most common forms of cancer in Veterans. In the metastatic setting, immunotherapy has emerged as a powerful oncologic treatment modality capable of producing durable control in all of these diseases. Unfortunately, the vast majority of Veterans do not benefit from this therapy, and thus, our long-term goal is to develop integrated treatment strategies with radiotherapy to enhance the efficacy of immunotherapy. The overall objective of this proposal is to define the importance of cell death induced by radiotherapy on immunotherapy efficacy. The central hypothesis of this proposal is that enhancing immunostimulatory radiation-induced ferroptosis will enhance immunotherapy efficacy. The rationale for this proposal comes from our published and unpublished data revealing that radiotherapy induces tumoral ferroptosis and the observation that radiotherapy and immunotherapy synergize to promote tumor control through ferroptosis. Beyond this, our results suggest that ferroptosis may be an immunogenic form of cell death. This hypothesis will be assessed and leveraged therapeutically to design rational combinatorial strategies using radiotherapy and immunotherapy in 3 aims. Aim 1 will define the molecular mediators (Aim 1A-C) and signaling pathways (Aim 1D) by which radiation-induced lipid oxidation and ferroptosis modulates anti-tumoral immunity. Aim 2 will determine the innate (Aim 2A, B) and adaptive (Aim 2C) cellular mediators by which radiation-induced lipid oxidation and ferroptosis regulate anti-tumoral immunity. Aim 3 will develop therapeutic strategies for modulating radiotherapy-induced ferroptosis to systemically augment immune checkpoint blockade efficacy (abscopal responses) in primary (Aim 3A) and metastatic (Aim 3B) melanoma tumor models. Furthermore, we will develop pharmacodynamic biomarkers (Aim 3C) of efficacy. The research proposed is innovative because the immunogenicity of ferroptosis has yet to be characterized. The completion of these aims is significant because it will establish a novel mechanistic link between ferroptosis, cytotoxic oncologic treatment modalities, and immune polarization, which can be leveraged therapeutically to improve immunotherapy efficacy in Veterans.