Lactate transporter MCT1 is required for the high suppressive function of tumor infiltrating regulatory T cells Abstract Cancer immunotherapy has revolutionized the way we treat cancer, but most patients fail to respond due to several resistance mechanisms including the recruitment, proliferation, and differentiation of regulatory T (Treg) cells in the tumor microenvironment (TME). While cytotoxic effector T (Teff) cells are rendered dysfunctional by the TME, the natural immunosuppressive function of Treg cells remains intact. Treg and Teff cells exhibit distinct metabolisms which may explain the discrepancy in their function within the TME. Metabolically, the TME is characterized by hypoxia, low pH, and limiting metabolites such as glucose and amino acids. While the highly glycolytic Teff cells are in direct competition with the tumor for glucose, recent evidence suggests Foxp3, the lineage defining transcription factor of Treg cells, can reprogram metabolism of Treg cells to function in high lactate, low glucose environments. Hypothesizing that Treg cells were supported by lactic acid within the TME, we bred a mouse with a Treg specific deletion of the lactate transporter MCT1 (Slc16a1f/f Foxp3YFPCre) and inoculated them with B16 melanoma. Treg specific loss of MCT1 resulted in slowed tumor growth and increased survival without leading to systemic autoimmunity. Measuring lactic acid concentration, we observed high levels within B16 tumors relative to peripheral lymphoid tissues. While MCT1 is predominantly recognized to transport lactate, it has several other substrates, such as propionate and studies on colonic Treg cells suggest propionate enhances Treg cell function and differentiation. Preliminary data from our lab corroborate these results, showing Treg cells conditioned in propionate increased expression of Treg markers Nrp1 and Helios. However, from these observations two questions arise, 1) is MCT1 required for Treg cell function only in lactate high TMEs, and 2) how do non-lactate MCT1 substrates influence Treg cell metabolism? We hypothesize that MCT1 is required for intratumoral Treg cell function in lactate rich TMEs and that its substrates promote an oxidative metabolism and the expression of Treg cell signature genes. To address this hypothesis, first we will (1) determine the requirement of MCT1 for intratumoral Treg cell function in metabolically distinct TMEs. We will inoculate Slc16a1f/f Foxp3YFPCre mice with metabolically distinct melanoma cell lines and measure the impact on intratumoral Treg cell metabolism via Seahorse, and function via suppression assay. Second, we will (2) determine the impact of non-lactate MCT1 substrate propionate on Treg cell metabolism. Using Foxp3YFPCre mice we will isolate Treg cells then condition them in media containing propionate and measure the impact on metabolism via Seahorse and apply isotopic flux analysis to identifying how Treg cells utilize propionate. By understanding the role of MCT1 and its substrates for Treg cell metabolism and function we can better design therapies that specifically dampen intratumoral Treg cells and improve cancer immunotherapies. This training will prepare me for an academic post-doctoral and ultimately independent investigator position by enhancing my research and communication skills and deepening my knowledge of Treg cells in cancer.

Public Health Relevance

Despite the success of cancer immunotherapy most patients fail to respond due to several resistance mechanisms including the accumulation of immunosuppressive regulatory T cells within the tumor. As regulatory T cells are vital for preventing autoimmunity and maintaining immune homeostasis, strategies for hindering their function specifically within the tumor microenvironment must be developed. This project aims to improve cancer immunotherapy by identifying how regulatory T cells are metabolically fueled within the tumor microenvironment in the hopes of targeting this axis to hinder intratumoral regulatory T cell function.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Gondre-Lewis, Timothy A
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University of Pittsburgh
Schools of Medicine
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