Mitochondrial Regulation of Antitumor Immunity

PROJECT SUMMARY Cancer cells undergo mitochondrial and metabolic adaptations to meet heightened demands for energy, biosynthesis, and stress resistance crucial for proliferation, tumor expansion, and metastasis. However, the extent to which this reprogramming impacts their recognition and elimination by the immune system remains poorly understood. That is, the influence of a tumor's metabolic state on its local environment and its ‘immunogenicity’ is unclear. Identifying ways to enhance the immunogenicity of tumor cells, thus making them more susceptible to immune attack, is a pressing need for many cancer patients who do not respond to immunotherapies like immune checkpoint blockade (ICB). The overarching goal of this proposal is to address this gap by investigating how mitochondrial metabolites and nucleic acids influence tumor immunogenicity in various ways. During the initial funding cycle, the PIs made the exciting discovery that cancer cell immunogenicity can be altered by manipulating mitochondrial respiration through the activity of complex II (CII) of the electron transport chain (ETC), also known as succinate dehydrogenase (SDH). Mechanistically, inhibiting CII/SDH led to an increase in intracellular succinate, thereby enhancing tumor immunogenicity through boosted tumor antigen presentation, independent of interferon gamma (IFNγ) signaling. In both murine and human tumor models, inhibiting CII/SDH or treating cancer cells with exogenous succinate alone increased MHC-I levels and converted typically resistant tumors into sensitive ones that are susceptible to killing by anti-tumor T cells. This mechanism, seemingly simple yet impactful, induced epigenetic modifications by reducing histone demethylase activity, thereby augmenting expression of MHC-I and antigen processing and presentation genes. Modifying tumor cell mitochondrial metabolism or potentially increasing succinate in the tumor microenvironment holds promise for the development of novel anticancer therapies. In Aim 1, we will investigate how metabolites such as succinate influence the metabolic landscape of the tumor microenvironment and explore strategies to increase succinate levels in tumors, aiming to directly enhance tumor MHC/APP expression and responsiveness to ICB without inhibiting mitochondria, which can have detrimental side-effects. Aim 2 will delve into how CII/SDH inhibition increases the expression of interferon-stimulated genes (ISGs), dependent on mitochondrial nucleic acids, and assess its contribution to boosting tumor immunogenicity alongside succinate-driven epigenetic modifications. Lastly, in Aim 3, how elevated succinate levels truly impact antigen presentation in tumor cells will be examined by profiling the MHC-I peptidome, aiming to determine whether CII/SDH inhibition merely increases the abundance of presented peptides or alters their composition, potentially broadening the repertoire to include lower affinity antigens recognized by T cells. This multifaceted approach will provide crucial insights into the mechanisms underlying tumor immunogenicity and may pave the way for innovative immunometabolic therapeutic strategies aimed at enhancing anti-tumor immune responses and immunotherapy.