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.

在美国，肺癌的死亡人数超过了紧随其后的四种主要癌症的总和

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.