Lymphoid residency of Tcf-1+ CD8+ T cells during tumor vaccine responses

Project Summary Tumor immunotherapies represent the most exciting advance for cancer patients in recent decades. However, only a minor proportion of treated patients experience long-lasting benefits from current tumor immunotherapies. A subset of tumor-specific T lymphocytes carrying features of memory or progenitor T cells has been named “stem-like” T cells. These stem-like T cells are essential to sustain anti-tumor T cell immunity and are the major responder to several current tumor immunotherapies. Thus, a better understanding of these stem-like T cells will greatly facilitate the improvement of current therapies or the development of future tumor immunotherapies. Tissue-resident memory T cells (TRM) are a subset of non-circulating memory T cells initially discovered after acute infections. Recently, we have discovered that stem-like T cells differentiate into tissue-resident T cells inside tumor-draining lymph nodes, which is negatively associated with the response to tumor vaccine. In other words, a large number of stem-like T cells lose migratory capacity and are trapped inside tumor-draining lymph nodes. However, several open questions remain to be addressed regarding this newly discovered feature of stem- like T cells. For example, what is the lineage relationship between this TRM-stem T cell subsets and other T cells inside tumor-draining lymph nodes? Is there a connection between TRM-stem in TDLN and stem-like T cells inside the tumor microenvironment? Whether can we manipulate TRM program of stem-like T cells to boost tumor vaccine? In this application, we will use multiple well-established tumor models to track tumor-specific CD8+ T cell response in the presence and absence of tumor vaccination. We will answer this series of questions focusing on this unique T cell subset, i.e., TRM-stem. Further, our proposal will primarily focus on tumor-draining lymph nodes, which serve as a reservoir for tumor-specific stem-like T cells. Our proposed studies will greatly advance our understanding of stem-like T-cell biology. Importantly, we will establish a new targeting organ (tumor-draining lymph nodes) and a novel target (the lymphoid residency program of stem-like T cells) to boost the efficacy of tumor vaccine.