Discovery Methods for Functional Immune Niches in Cancer

PROJECT SUMMARY This study investigates the ‘reactive’ immune system in tumors, namely the cellular and molecular allies that allow immunotherapies to work. The tumor microenvironment (TME) is a key biological structure that regulates the effectiveness of cancer immunotherapies. Understanding its (rare) valuable components and niches as compared to the inhibitory ones is critical to guiding next-generation immunotherapies. We hypothesize that discrete niches exist in tumors that are the building blocks for reactive immunity and that these can be found by co-labeling T cell activity (e.g. motility/synapse duration) and gene-expression signatures together with unique innovative tools. By directly illuminating functional effector CD8 T cell states, we will discover hidden features of their local microenvironment and define these in such a way to be widely applicable in new settings. This program is unique in applying and developing spatial transcriptomics together with genetic tools and conventional cellular immunoassay methods to understand the critical phenotype-biology relationship between critical T cell populations and their partners. The resultant discoveries will be formative for designing new ways to boost anti-tumor immunity.