LAUSR

Tumor reliance on glycolysis is a hallmark of cancer and a mechanism of resistance to immunotherapy. This resistance is due to lactate-mediated immune suppression and competition for glucose between T cells and tumor cells within the tumor microenvironment. We have shown that CTLA-4 blockade is more effective in glycolysis-low tumors, or tumors lacking functional lactate dehydrogenase A (LDH-A), primarily due to functional destabilization of regulatory T cell suppression. LDH inhibitors (LDHi) have been reported to inhibit tumor glucose uptake and slow tumor cell proliferation in pre-clinical models of cancer. However, their effect on immune cells has not been explored in depth. In addition, the optimal conditions for pharmacological inhibition of LDH in combination with immunotherapy to maximize anti-tumor immune and therapeutic responses require further investigation. At baseline, tumor cells express higher levels of ldha and consume more glucose than tumor-infiltrating T cells, creating a therapeutic window for tumor-specific targeting of the glycolysis pathway. In vivo, LDHi relies on the adaptive immune system and the overexpression of tumor LDH to delay B16F10 murine melanoma progression. We found that treatment with LDHi has two effects: 1) reduction of tumor cell glucose uptake and 2) increase in glucose uptake by tumor-infiltrating T cells. Thus, LDH inhibition is an effective, tumor-specific strategy to reduce tumor cell glucose uptake and increase glucose availability within the tumor microenvironment, consequently boosting tumor-infiltrating T cell glucose uptake. In vitro, increased glucose levels improve effector T cell killing of tumor cells while reducing regulatory T cell suppressive ability. Accordingly, inhibiting LDH in combination with CTLA-4 blockade is more effective in controlling tumor progression compared to CTLA-4 blockade alone, and that this combination promotes effector T cell infiltration and activation, while destabilizing regulatory T cell function. Additionally, we observe serum LDH and lactate levels correlate with primary tumor burden as well as tumor LDH levels. Therefore, serum LDH may serve as a biomarker for tumor burden and tumor LDH, as well as clinical response to LDHi. This study provides a comprehensive rationale for combining immune checkpoint blockade with inhibitors of glycolysis for patients with highly glycolytic cancers. Citation Format: Svena Verma, Inna Serganova, Lauren Dong, Sadna Budhu, Levi Mangarin, Roberta Zappasodi, Taha Merghoub, Jedd D. Wolchok. LDH inhibition boosts effector T cells while destabilizing regulatory T cells and improves responses to CTLA-4 blockade. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5873.