Hi-jacking the kynurenine pathway: A new path used by cisplatin resistant non-small cell lung cancer to survive and evade immune surveillance under high ROS

劫持犬尿氨酸途径：顺铂耐药非小细胞肺癌在高ROS下生存和逃避免疫监视的新途径

• 批准号: 10266010
• 负责人: Medhi Wangpaichitr
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266010
• 关键词: Affect; Amino Acids; Attention; Biochemical; Biological Assay; Cancer Patient; Carboplatin; Catabolism; Cell Death; Cells; Cessation of life; Cisplatin; Consumption; Detection; Development; Diagnosis; Disease; Disease remission; Drug resistance; Early treatment; Environment; Equilibrium; FOXP3 gene; Future; Glucose; Glutamine; Glycolysis; Growth; HIF1A gene; Healthcare Systems; Human; IL2RA gene; Immune; Immune response; Immune system; Immunocompetent; Immunologic Surveillance; Immunotherapy; Incidence; Knowledge; Kynurenine; Lactic acid; Lead; Liquid substance; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Modality; Mus; Non-Small-Cell Lung Carcinoma; Nutrient; Operative Surgical Procedures; Oxidative Stress; Oxides; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Platinum; Play; Pleural; Population; Production; Proliferating; Proteins; Radiation therapy; Reactive Oxygen Species; Regimen; Regulatory T-Lymphocyte; Reporting; Resistance; Role; Serum Markers; Signal Transduction; Systemic Therapy; T-Lymphocyte; Time; Transcript; Transplantation; Tryptophan; Tryptophan 2,3 Dioxygenase; United States; United States Department of Veterans Affairs; Veterans; Warburg Effect; Work; aerobic glycolysis; analog; base; chemotherapeutic agent; chemotherapy; cytotoxic; effective therapy; effector T cell; improved; inhibitor/antagonist; lung cancer cell; novel strategies; novel therapeutic intervention; prevent; programmed cell death protein 1; response; tumor; tumor metabolism; tumor microenvironment

The toll of lung cancer deaths in the United States exceeds that of the next four major cancers combined, and is the most common cancer found in veterans. Not only is the incidence higher, but the survival is lower than in civilian populations. Surgery is the main treatment for early stage lung cancer, but most patients already have locally advanced or metastatic disease at the time of diagnosis. Subsequently, chemotherapy or combined chemotherapy with radiation therapy remains the primary modality of treatment. Immunotherapy with check point inhibitors (PD-1) has received much attention lately, offering a longer duration of response. However, the response rate is still low in lung cancer. In fact, a recent report on these immunotherapy treatment did not show improved efficacy over standard chemotherapy and failed as first line treatment in lung cancer. Therefore, the majority of lung cancer patients still require traditional chemotherapeutic agents that affect proliferating cells such as cisplatin or carboplatin for control of their disease. Despite early positive responses to platinum-based chemotherapy, the majority of lung cancer patients develop drug resistance, and cisplatin resistance remains the major obstacle for the effective treatment of lung cancer. For the past three decades, no drugs have reversed cisplatin resistance or selectively killed non-small cell lung cancer cisplatin resistant (CR) cells. We discovered that CR cells possess higher basal level of reactive oxygen species (ROS) and do not follow classic aerobic glycolysis (Warburg effect), but instead consume a higher rate of glutamine and tryptophan. Consequently, the tumor microenvironment accommodates lower levels of amino acids and becomes unfavorable for cytotoxic T-effector cells (T-eff) which are highly anabolic and also require high amounts of nutrients to expand. With this understanding, we have discovered that CR cells activate the kynurenine pathway (L-tryptophan catabolism) in order to cope with higher ROS concentrations during their growth and proliferation, making this pathway essential for their survival. Importantly, L-kynurenine (KYN), a product of the kynurenine pathway, plays a key role in reprogramming naïve T-cells to the immune suppressive regulatory T-cell (T-reg) phenotype. Thus, creating an environment in which CR tumors are able to proliferate and escape from the immune system. In this application, we plan to further confirm and exploit these crucial findings by: First; establishing how the activated kynurenine pathway (KP) shields cisplatin resistant non-small cell lung cancer from immune surveillance and enhances cisplatin resistance. Second; determining how metabolic reprogramming can lead to alterations in the tumor microenvironment favoring immunosuppressive T-cells in CR tumors. Third; overcoming cisplatin resistance by inhibiting KP. Fourth; identifying the population of lung cancer patients who will be benefit greatly from the combination of chemo + immunotherapy, among the patients who fail first line cisplatin containing regimen. Recognizing the interrelationship between tumor metabolism and the immune response is extremely critical to the development of better systemic therapies. Our proposed work will serve as a novel approach to overcome cisplatin resistance by exploiting primary biochemical differences of resistant tumors, and to provide knowledge on: (i) how to effectively exploit the KP pathway to treat CR tumors, (ii) whether blocking the KP pathway can impede the development of platinum resistance (iii) understanding how CR cells evade immune surveillance, (iv) identify possible serum markers which can be used to select patients for future treatment using KP inhibitors. Overall, we have uncovered a new pathway which CR cells use to survive and proliferate; consequently, blocking this pathway will lead to cell death and more effective treatment of lung cancer.

美国肺癌死亡人数超过了接下来四种主要癌症的总和， 退伍军人中最常见的癌症不仅发病率更高，而且生存率也低于退伍军人。 手术是早期肺癌的主要治疗方法，但大多数患者已经患有这种疾病。 诊断时患有局部晚期或转移性疾病，随后进行化疗或联合治疗。 化疗联合放射治疗仍然是免疫治疗联合检查点的主要方式。 抑制剂（PD-1）最近受到了广泛关注，但其反应持续时间较长。 事实上，最近关于这些免疫疗法的报告并未显示肺癌的缓解率。 与标准化疗相比，其疗效有所提高，但作为肺癌的一线治疗失败了。 大多数肺癌患者仍然需要影响增殖细胞的传统化疗药物，例如 尽管早期对铂类药物有积极反应，但仍使用顺铂或卡铂来控制疾病。 化疗后，大多数肺癌患者产生耐药性，顺铂耐药性依然存在 是肺癌有效治疗的主要障碍。 在过去的三十年里，没有任何药物可以逆转顺铂耐药性或选择性杀死非小细胞肺癌。 我们发现CR细胞具有较高的基础反应水平。 氧物种（ROS）并且不遵循经典的有氧糖酵解（瓦尔堡效应），而是消耗 检测到的谷氨酰胺和色氨酸比例较高，肿瘤微环境适应的水平较低。 氨基酸的减少，对细胞毒性 T 效应细胞 (T-eff) 不利，因为细胞毒性 T 效应细胞具有高度合成代谢能力，而且 需要大量的营养物质才能扩张，我们发现 CR 细胞会激活。 犬尿氨酸途径（L-色氨酸分解代谢），以应对较高的 ROS 浓度 重要的是，L-犬尿氨酸（KYN）是一种生长和增殖的途径。 犬尿氨酸途径的产物，在将幼稚 T 细胞重编程为免疫抑制中发挥着关键作用 调节性 T 细胞 (T-reg) 表型，从而创造 CR 肿瘤能够增殖的环境。 并逃离免疫系统。 在此应用中，我们计划通过以下方式进一步确认和利用这些重要发现：首先； 激活的犬尿氨酸通路 (KP) 可保护顺铂耐药的非小细胞肺癌免受免疫影响 其次，确定代谢重编程如何导致顺铂耐药。 肿瘤微环境的改变有利于 CR 肿瘤中的免疫抑制 T 细胞的克服。 第四，通过抑制 KP 来确定哪些肺癌患者会受益。 一线顺铂治疗失败的患者中，很大程度上来自化疗+免疫治疗的组合 包含方案。 认识肿瘤代谢与免疫反应之间的相互关系非常重要 我们提出的工作对于开发更好的系统疗法至关重要。 通过利用耐药肿瘤的主要生化差异来克服顺铂耐药性，并提供 知识：（i）如何有效利用KP通路治疗CR肿瘤，（ii）是否阻断KP 途径可以阻碍铂耐药的发展 (iii) 了解 CR 细胞如何逃避免疫 监测，(iv) 确定可能的血清标志物，可用于选择患者进行未来的治疗 总的来说，我们发现了 CR 细胞生存和增殖的新途径； 因此，阻断这一途径将导致细胞死亡和更有效的肺癌治疗。

项目成果

Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma.

• DOI: 10.1002/cncr.32339
• 发表时间: 2019-10-15
• 期刊: Cancer
• 影响因子: 6.2
• 作者: Feun LG;Li YY;Wu C;Wangpaichitr M;Jones PD;Richman SP;Madrazo B;Kwon D;Garcia-Buitrago M;Martin P;Hosein PJ;Savaraj N
• 通讯作者: Savaraj N

Exploiting the Innate Plasticity of the Programmed Cell Death-1 (PD1) Receptor to Design Pembrolizumab H3 Loop Mimics.

• DOI: 10.1002/cbic.202200449
• 发表时间: 2022-11-04
• 期刊: CHEMBIOCHEM
• 影响因子: 3.2
• 作者: Richaud, Alexis D.;Zaghouani, Mehdi;Zhao, Guangkuan;Wangpaichitr, Medhi;Savaraj, Niramol;Roche, Stephane P.
• 通讯作者: Roche, Stephane P.