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 nave 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.
Lung cancer is the most common cancer found in the Veterans Affairs Healthcare System. Cisplatin or its analog carboplatin is one of the main drugs which has been utilized for the treatment of this disease. Development of platinum resistance is inevitable and hinders the likelihood of achieving remission and hence leads to poor survival. We have found that (CR) cisplatin resistant lung cancer cells express higher baseline levels of oxidative stress and undergo metabolic reprogramming. They do not depend on glycolysis, but rather utilize amino acids. In this proposal, we have discovered that CR cells activate kynurenine pathway to cope with ROS and use this pathway as immune escape mechanism. Thus, by identifying and targeting this pathway, CR tumors can be selectively killed. Our study will not only represent a new avenue for eradicating cisplatin resistant tumors but also broaden our knowledge how to improve immunotherapy treatment.
