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是五种癌症中的四种。 退伍军人中最常见的癌症。在转移的背景下，免疫疗法已经成为一种 强大的肿瘤学治疗模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治疗策略，以提高免疫治疗的疗效。这个 这项提案的总体目标是确定放射治疗引起的细胞死亡的重要性 免疫治疗的疗效。这一提议的中心假设是增强免疫刺激 放射性铁下垂将提高免疫治疗的疗效。提出这项建议的理由是 我们已发表和未发表的数据显示，放射治疗导致肿瘤性铁下垂和 观察放射治疗和免疫治疗通过铁性下垂促进肿瘤控制的协同作用。 除此之外，我们的结果表明，铁性下垂可能是一种免疫原性的细胞死亡形式。这一假设 将被评估并在治疗上利用放射治疗来设计合理的组合策略 免疫治疗3个靶点。目标1将定义分子介体(目标1A-C)和信号通路 目的1D辐射诱导的脂质氧化和铁下垂通过其调节抗肿瘤免疫。目标2将 确定辐射诱导脂质的先天(目标2A，B)和适应性(目标2C)细胞介质 氧化和铁下垂调节抗肿瘤免疫。AIM 3将制定治疗策略 调节放射治疗引起的铁性下垂系统增强免疫检查点阻断效果 (异常反应)在原发(目标3A)和转移性(目标3B)黑色素瘤肿瘤模型。此外，我们 将开发疗效的药效学生物标记物(AIM 3C)。提出的这项研究具有创新性，因为 铁性上睑下垂的免疫原性尚不清楚。这些目标的实现意义重大。 因为它将在铁性下垂、细胞毒性肿瘤治疗方式、 和免疫极化，可以在治疗上利用这一点来提高免疫治疗的疗效 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 The rationale for this proposal comes from our published and unpublished data revealing that radiotherapy induces tumoral ferroptosis and the observation that radiotherapy and immunotherapy synergize to promote tumor control through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.