Membrane-localised mutations predict the efficacy of cancer immunotherapy

ABSTRACT Due to their genetic instability, tumor cells bear mutations that can effectively be recognized by the immune system. In the clinic, immune checkpoint immunotherapy (ICI) can re-activate immune reactions against mutated proteins, known as neoantigens, leading to remarkable remission in cancer patients. Nevertheless, only a minority of patients are responsive to ICI, and approaches for prediction of responsiveness remain elusive yet are needed to improve the success of cancer treatments. While the tumor mutational burden (TMB) correlates positively with responsiveness and survival of patients undergoing ICI therapy, the influence of the subcellular localizations of the mutated proteins within the tumor cell has not been elucidated. Here, we hypothesized that the immune reactions are modulated by the localization of the mutated proteins and, therefore, that some subcellular localizations could favor responsiveness to ICI. We show in both a mouse melanoma model and human clinical datasets of 1722 ICI-treated patients that high membrane-localized tumor mutational burden (mTMB), particularly at the plasma membrane, correlate with responsiveness to ICI therapy and improved overall survival across multiple cancer types. We further highlight that mutations in the genes encoding for the membrane proteins NOTCH3, RNF43, NTRK3 and NOTCH1 , among others, may serve as potent biomarkers to predict extended survival upon ICI in certain cancer types. We anticipate that our results will improve the predictability of cancer patient response to ICI and therefore may have important implications to establish future clinical guidelines to direct the choice of treatment toward ICI.