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

在美国，肺癌死亡人数超过了接下来的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，而且生存率也比 平民手术是早期肺癌的主要治疗方法，但大多数患者已经 诊断时为局部晚期或转移性疾病。随后，化疗或联合 化疗和放射治疗仍然是主要的治疗方式。检查点免疫治疗 PD-1抑制剂最近受到了广泛关注，提供了更长的反应持续时间。但 肺癌的缓解率仍然很低。事实上，最近的一份关于这些免疫疗法治疗的报告并没有显示 与标准化疗相比提高了疗效，但作为肺癌的一线治疗失败。因此 大多数肺癌患者仍然需要影响增殖细胞的传统化疗剂 如顺铂或卡铂来控制他们的疾病。尽管早期对铂基 化疗后，大多数肺癌患者产生耐药性，顺铂耐药性仍然存在， 有效治疗肺癌的主要障碍。 在过去的三十年里，没有药物逆转顺铂耐药性或选择性杀死非小细胞肺癌。 细胞肺癌顺铂耐药（CR）细胞。我们发现CR细胞具有更高的基础反应水平， 氧物种（ROS），并不遵循经典的有氧糖酵解（瓦尔堡效应），而是消耗 谷氨酰胺和色氨酸的比例较高。因此，肿瘤微环境容纳较低水平的 并且变得不利于细胞毒性T效应细胞（T-eff），所述细胞毒性T效应细胞（T-eff）是高度合成代谢的， 需要大量的营养来膨胀有了这种理解，我们发现CR细胞激活 犬尿氨酸途径（L-色氨酸催化剂），以科普在其代谢过程中较高的ROS浓度。 生长和增殖，使这一途径对它们的生存至关重要。重要的是，L-犬尿氨酸（KYN）， 犬尿氨酸途径的产物，在将幼稚T细胞重编程为免疫抑制性T细胞中起关键作用。 调节性T细胞（T-reg）表型。因此，创造CR肿瘤能够增殖的环境， 从免疫系统中逃脱 在这个应用程序中，我们计划通过以下方式进一步确认和利用这些关键发现：首先，确定如何 激活的犬尿氨酸途径（KP）保护顺铂耐药的非小细胞肺癌免受免疫抑制， 监测和增强顺铂耐药性。第二，确定代谢重编程如何导致 肿瘤微环境的改变有利于CR肿瘤中的免疫抑制性T细胞。第三，克服 顺铂耐药的抑制KP。第四，确定受益的肺癌患者人群 在一线顺铂治疗失败的患者中， 包含方案。 认识到肿瘤代谢和免疫反应之间的相互关系是非常重要的。 这对开发更好的系统治疗至关重要。我们提出的工作将作为一种新的方法， 通过利用耐药肿瘤的主要生化差异克服顺铂耐药性，并提供 了解：（i）如何有效利用KP途径治疗CR肿瘤，（ii）是否阻断KP途径 （iii）了解CR细胞如何逃避免疫反应， 监测，（iv）确定可能的血清标志物，可用于选择患者进行未来治疗， KP抑制剂。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，从而更有效地治疗肺癌。

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.