Defining mechanisms to promote antitumor immunity by modulating one-carbon metabolism

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Immune checkpoint blockade (ICB) targeting PD-1 and its ligand PD-L1 has revolutionized cancer therapy, but only a subset of patients respond, highlighting the critical need to investigate mechanisms of anti-tumor immunity to identify novel targets to enhance the effects of ICB. The goal of this project is to determine mechanisms by which one-carbon (1C) metabolism can be modulated to improve the efficacy of PD-1 blockade. We recently identified 1C metabolism, which allows cells to utilize serine or glycine to generate 1C units for nucleotides, NADPH, and glutathione biosynthesis, as the most induced metabolic pathway during T cell activation. We also discovered that there are deficits in serine and glucose levels in the tumor microenvironment (TME). Strikingly, restoring 1C metabolism by formate supplementation increases the effectiveness of anti-PD-1 treatment and tumor clearance in mouse tumor models. We hypothesize that 1C metabolism is limiting for anti-tumor T cell function and that increasing this pathway by formate supplementation can synergize with ICB to promote anti-tumor immunity. We will test this hypothesis in two aims: Aim 1: Determine cellular and molecular mechanisms by which formate supplementation improves the efficacy of PD-1 mediated tumor clearance. We will define transcriptional and epigenetic mechanisms by which 1C metabolism and formate supplementation improve CD8+ T cell function and synergize with PD-1 blockade. We will use innovative conditional knockout models and in vivo genetic perturbation studies to delete rate- limiting enzymes of 1C metabolism in CD8+ T cells, and analyze their impact on response to PD- 1 blockade. Aim 2: Determine metabolic mechanisms by which formate supplementation improves the efficacy of PD-1 mediated tumor clearance. We will use cellular and in vivo mass spectrometry-based metabolite tracing studies, and spatial metabolomics to elucidate how formate supplementation and modulation of 1C metabolism impact metabolic profiles of anti- tumor CD8+ T cells when combined with anti-PD-1. These studies will provide us with the first spatial and single cell resolution atlas of metabolic and functional immune responses in a tumor in response to ICB. We will determine how formate supplementation improves CD8+ T cell responses from the level of individual CD8+ T cells to CD8+ T cells in the metabolically heterogenous TME. Completion of these studies will be transformative by changing the paradigm of 1C metabolism in cancer treatment and demonstrating that supplementing 1C units can enhance anti-tumor immunity. Our results will inform strategies and identify novel therapeutic targets for improving cancer immunotherapy outcomes.