Date of Award
Spring 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Cellular and Molecular Physiology
First Advisor
Perry, Rachel
Abstract
Melanoma is the deadliest skin cancer type, causing 8000 deaths per year in the United States. The development of immunotherapy significantly prolongs the survival of cancer patients, including patients with melanoma. By impairing the inhibitory signaling pathway, immunotherapy, for example anti-PD-1 monoclonal antibody, reinforces the anti-tumor effector function of T cells that recognize cancer cells and therefore suppresses tumor progression. However, the problem of low responsiveness and development of resistance significantly prevents a large proportion of patients from benefiting from immunotherapy. Therefore, it is of great importance to develop adjuvants to increase the efficacy of immunotherapy. Metabolic alterations have long been identified as a key regulator in tumor progression as well as immune cell function and therefore studied as a therapeutic target to control tumor growth. Previous studies have shown that T cell activation and function is regulated by metabolic conditions within the microenvironment. Although unlike other cancer types, for instance breast cancer and colon cancer, melanoma is not considered as obesity-associated cancer, which leads to limited response to metabolic treatments both in vivo and in vitro, some recent clinical observations of higher anti-PD-1 immunotherapy efficacy in melanoma patients with obesity suggest a correlation between metabolism and T cell reinforcement in melanoma. Revealing the underlying mechanism may shed new light to the development of adjuvants to increase immunotherapy efficacy. Therefore, in this dissertation, we focused on metabolism-targeting therapeutics and re-targeting them to cancer treatments. We first compared endogenous metabolic patterns between two murine melanoma models with distinct immunogenicity, the ability to elicit anti-tumor immune response, and identified different glucose and glutamine metabolic preferences. This results also indicate the impact of nutrient availability within tumor microenvironment on both inhibitory signals produced by tumor cells and the effector function of infiltrated immune cells. We then identified thiazolidinedione (TZD), an FDA-approved drug for diabetes that increases insulin sensitivity and alters fatty acid metabolism, as an immunotherapy enhancer in murine melanoma model. We found that by reducing inhibitory PD-1 expression either directly or indirectly via reduced insulin and increased NEFA content in tumor tissue, TZD promotes the reinforcement of anti-tumor immune cells. We also surprisingly discovered the effect of dichloroacetate (DCA), a small molecule glucose oxidation enhancer, on relieving cancer-related fatigue, which is, to our knowledge, the first pharmaceutical treatment targeting this condition. We showed that DCA preserves both physical performance of muscle tissue and motivation for movement by reducing circulating lactate concentration, in addition to a potential effect on reducing oxidative stress in muscle tissue. Eventually, we conducted literature review about cancer-related fatigue and its potential metabolic causes, majorly focusing on obesity and insulin resistance, providing new potential therapeutic targets for cancer complication control. In sum, this dissertation studied the metabolic effect on anti-tumor immune cells in murine melanoma models and developed metabolism-targeting adjuvants to current treatments, revealing new therapeutic approaches to both reduce tumor growth and relieve cancer-related fatigue.
Recommended Citation
Zhang, Xinyi, "Developing metabolism-targeting adjuvants to immunotherapy in murine melanoma" (2024). Yale Graduate School of Arts and Sciences Dissertations. 1475.
https://elischolar.library.yale.edu/gsas_dissertations/1475
