Metabolic predictors of response to immune checkpoint blockade therapy

Metabolism of immune cells in the tumor microenvironment (TME) plays a critical role in cancer patient response to immune checkpoint inhibitors (ICI). Yet, a metabolic characterization of immune cells in the TME of patients treated with ICI is lacking. To bridge this gap we performed a semi-supervised analysis of ∼1700 metabolic genes using single-cell RNA-seq data of > 1 million immune cells from ∼230 samples of cancer patients treated with ICI. When clustering cells based on their metabolic gene expression, we found that similar immunological cellular states are found in different metabolic states. Most importantly, we found metabolic states that are significantly associated with patient response. We then built a metabolic predictor based on a dozen gene signature, which significantly differentiates between responding and non-responding patients across different cancer types (AUC = 0.8–0.92). Taken together, our results demonstrate the power of metabolism in predicting patient response to ICI. [Display omitted] •Immune cells in the tumor microenvironment show metabolic heterogeneity•CD8+ T cells with similar immunological state can demonstrate metabolic differences•A metabolic gene signature is capable of predicting patient response to ICI•A unique tumor metabolic signature contributes to acquired ICI resistance Human metabolism; Immunology; Cancer