Prophylactically-induced brain-resident memory CD8+ T cells provide durable protection against intracranial malignancy 2089

Abstract Description Primary and metastatic brain tumors are clinically refractory to immunotherapies that demonstrate efficacy in peripheral cancer settings. While many immunotherapies aim to enhance CD8+ T cell infiltration and functionality in fully established tumors, the utility of immunoprevention against brain cancer remains understudied. Numerically enriched and functionally potent tissue-resident memory (TRM) CD8+ T cells can be generated in healthy brain tissue following peripheral infection and vaccination. However, the ability of prophylactically-seeded, tumor-specific brain TRM to protect against intracranial malignancy remains unknown. Here, we developed models where mice were seeded with tumor-specific or bystander brain TRM via peripheral infection prior to brain tumor challenge. Tumor-specific, but not bystander, brain TRM durably protected mice against intracranial malignancy even in the absence of circulating memory T cells (TCIRCM). These brain TRM persisted long-term in tumor survivors and prevented mortality against a second antigen-matched intracranial challenge. Importantly, a translationally relevant mRNA vaccine encoding tumor-derived epitopes phenocopied peripheral infection-induced outcomes, generating functional brain TRM that intercepted tumor growth. Altogether, this work points to the prophylactic utility of brain TRM in tumor immunoprevention and supports the development of anti-cancer mRNA vaccines as a non-invasive approach to bolster brain immunity. Funding Sources NIH/NIAID R21AI178159 NIH/NIAID R21AI185067 NIH/NIAID T32AI007260 NIH/NIGMS T32GM139776 NIH/NIAID F32AI174382 University of Iowa Graduate College Post-Comprehensive Research Fellowship Topic Categories Neuroimmunology (NEUR)