Hypoxia-Induced Lactate Production By Tumor-Associated Macrophages Promote Tumorigenesis.

Abstract Tumor-associated macrophages (TAMs) are the most prevalent immune cell in the tumor microenvironment (TME). They mainly adopt an M2-like phenotype that supports angiogenesis, attenuates anti-tumor immunity, and promotes metastasis. Blocking M2 activation of TAMs in pre-clinical models attenuates tumor growth and metastasis, and high abundance of M2-like TAMs is associated with poor patient survival across many cancer types. Despite of TAMs as a promising therapeutic target, the mechanisms producing their M2-like phenotype is poorly understood. This understanding is required to develop effective TAM-targeting therapeutics and identify patients that might benefit from them. One potential pathway to influence macrophage polarization is via metabolic reprogramming. The traditional view is that glycolysis supports a pro-inflammatory M1 phenotype in macrophages, while oxidative phosphorylation is required for their M2 phenotypes. Our recent work challenged this paradigm. We showed that treating macrophages with LPS or bacteria (conditions that support M1 activation) induces lactate production, which in turn drives a late phase switch to an M2-like phenotypes. The mechanism underlying this surprising observation involves a novel lactate-induced epigenetic modification termed histone lysine lactylation (Kla) that marks promoters of M2-like genes and directly promote transcription. In tumors, hypoxia is a key environmental stimulus that induces lactate production. The goal of this study was to examine if hypoxia-induced lactate production by TAMs metabolically reprograms them to promote Kla-M2 pathway to influence tumorigenesis. Here, we showed that hypoxia-induced lactate production by macrophages elevates the expression of M2-like genes, marked by Kla at their promotes. We further demonstrated the spatial and quantitative relationship between hypoxia, Kla, and M2-like phenotype within a single tumor (GEM model & human tumors) and across tumors with variable hypoxia (syngeneic models). Moreover, inhibiting endogenous lactate production by TAMs (via Ldha deletion) reduces tumor growth, attenuates M2-like phenotype of TAMs, and increases CD8+ T cells in tumor with high hypoxia, but not low hypoxia. Importantly, lactate level in TME is independent of tumor hypoxia or LDHA status, suggesting that this epigenetic pathway is primarily driven by endogenous lactate production by TAM rather than exogenous lactate in TME. Collectively, our studies demonstrated an important role for a “hypoxia-induced lactate-Kla-M2 pathway” in TAMs to promote tumorigenesis. Citation Format: Chang Cui, kasturi Chakraborty, Kelly Schoenfelt, Guolin Zhou, Xu Anna Tang, Catherine Reardon, Di Zhang, Alexander Muir, Yingming Zhao, Lev Becker. Hypoxia-induced lactate production by tumor-associated macrophages promote tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2766.