Abstract
Abstract The treatment of melanoma has been fundamentally changed by immunotherapies like blockade of coinhibitory “checkpoint” molecules like CTLA-4 and PD-1. However, despite these remarkable successes, even within T cell-inflamed, high-mutational-burden tumors, response rates remain low, likely due to additional immune inhibitory mechanisms present in the tumor microenvironment. It is now generally appreciated that the tumor microenvironment is characterized by a distinct metabolic landscape, having low oxygen tension, depleted levels of essential nutrients, and buildup of toxic byproducts. We sought to determine whether this metabolic landscape was variable from patient to patient and how this landscape affected antitumor immunity and thus response to immunotherapy. Using extracellular metabolic flux analysis, we profiled the metabolic derangement of patient-derived cell lines as well as direct ex vivo patient tumor samples, revealing striking heterogeneity not only in the degree of metabolic derangement but also in the type of metabolism a tumor cell was dependent on. Analysis of the tumor infiltrate revealed that a tumor’s preference for oxidative metabolism was associated with immune dysfunction, suggesting that the ability to generate hypoxic regions in vivo is a key aspect of immune resistance. We confirmed this finding in vivo using a novel model of melanoma in which individual metabolic pathways can be selectively targeted in a single-cell derived line: loss of oxidative metabolism in tumor cells sensitizes animals to PD-1 blockade immunotherapy, while loss of glycolytic metabolism has no appreciable effect on antitumor immunity. Analysis of melanoma patient biopsy samples prior to initiation of immunotherapy revealed that increased tumor oxidative metabolism and intratumoral hypoxia was associated with poorer responses to checkpoint blockade. Our data highlight the use of tumor microenvironment hypoxia as a potential predictor of immunotherapy resistance and shed light on the use of modulators of tumor cell oxidation as a means to improve responses to checkpoint blockade. Citation Format: Greg M. Delgoffe. Tumor cell oxidative metabolism as a barrier to antitumor immunity in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA09.
Published Version
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