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中的四种 退伍军人中最常见的癌症在转移背景下，免疫疗法已成为一种 强大的肿瘤治疗模式，能够在所有这些疾病中产生持久的控制。 不幸的是，绝大多数退伍军人没有从这种治疗中受益，因此，我们的长期目标是 发展放射治疗的综合治疗策略，以提高免疫治疗的疗效。的 本提案的总体目标是确定放射治疗诱导细胞死亡的重要性， 免疫治疗效果。该建议的中心假设是，增强免疫刺激性， 辐射诱导的铁凋亡将增强免疫疗法的功效。这一提议的理由来自于 我们已发表和未发表的数据显示，放射治疗可诱导肿瘤铁凋亡， 观察到放射治疗和免疫治疗协同作用，通过铁凋亡促进肿瘤控制。 除此之外，我们的研究结果表明，铁凋亡可能是一种免疫原性形式的细胞死亡。这一假设 将进行评估，并在治疗上加以利用，以设计合理的组合策略， 免疫治疗3个目标。目标1将定义分子介质（目标1A-C）和信号通路 (Aim 1D）通过辐射诱导的脂质氧化和铁凋亡调节抗肿瘤免疫。目标2将 确定辐射诱导脂质代谢的先天性（Aim 2A，B）和适应性（Aim 2C）细胞介质 氧化和铁凋亡调节抗肿瘤免疫。目标3将制定治疗策略， 调节放射疗法诱导的铁凋亡以全身性地增强免疫检查点阻断功效 在原发性（Aim 3A）和转移性（Aim 3B）黑色素瘤肿瘤模型中，而且我们 将开发疗效的药效学生物标志物（目标3C）。这项研究具有创新性，因为 铁凋亡的免疫原性还有待鉴定。这些目标的完成意义重大 因为它将在铁下垂，细胞毒性肿瘤治疗方式， 和免疫极化，这可以在治疗上被利用来改善免疫治疗的功效， 老兵

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 The rationale for this proposal comes from our published and unpublished data revealing that radiotherapy induces tumoral ferroptosis and the observation that radiotherapy and immunotherapy synergize to promote tumor control through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.