Unlocking the tissue code: Understanding organ-specific regulation of CD8+ T cell immunity by eicosanoids

forthcoming

CD8+ T cells are critical for immunity against infection and cancer. Eliciting protective CD8+ T cell immunity is the main goal of many current and emerging immunotherapies aimed at treating these diseases, holding the promise to substantially improve patient outcomes. Evidence suggests that T cell regulation by tissue-derived factors is one of the key mechanisms influencing the protective potential of CD8+ T cell responses, however, the nature and molecular impact of these factors remains incompletely understood. Building on our recent work, I propose that organ-specific regulation of CD8+ T cell immunity is driven by eicosanoids, a class of bioactive lipids, which act as tissue factors that locally shape CD8+ T cell differentiation and function. EICO-CODE aims to understand how eicosanoids shape CD8+ T cell responses in organs and to reveal their mechanistic implications for T cell immunity against cancer and viral infections. We will use newly developed methods for eicosanoid profiling and T cell eicosanoid sensing to define eicosanoid profiles across organs and identify how these locally provided factors are sensed by CD8+ T cells. We will further integrate approaches for T cell gene editing, T cell barcoding and single-cell RNA-sequencing with a unique set of organ-specific cancer and viral infection models, to reveal how eicosanoids modulate anti-cancer and anti-viral CD8+ T cell responses and test how this determines their protective potential. This project will provide new mechanistic links between organ-derived bioactive lipid mediators and T cell immunity. These insights will influence our current understanding of how immune responses are adapted in different tissues and will help to identify new molecular targets and therapeutic strategies to enhance or reinvigorate protective immunity against cancer or infection.