EXPANDing Immune Cells and their Tumor Antigens during checkpoint immunotherapy

Cancer immunotherapy using immune checkpoint blockade (ICB) has revolutionized the treatment of advanced-stage cancers. One of the major limitations of ICB is that durable responses are observed only in a subset of patients and in some specific cancer types. We recently analyzed tumor biopsies from breast cancer patients collected during ICB and indeed observed only in a subset of patients that tumor-infiltrating T-cells undergo rapid expansion when exposed to ICB. We characterized the gene expression programs underlying this expansion at single-cell level and realized that - although these expanding T-cells are the main executors of therapeutic response to ICB - several key questions regarding their function remain unanswered. First, we lack accurate knowledge about where in the heterogeneous tumor microenvironment (TME) and in which metabolic niches T-cell expansion occurs. Secondly, based on their TCR sequence we cannot predict upfront which T-cells will expand (or rather act as bystander T-cells), nor can we say to which tumor antigens these expanding T-cells are directed. Thirdly, it is not known which molecular events underlie the generation of the tumor antigens regulating T-cell expansion. Fourthly, we also observed an expansion of the B-cell repertoire and were left with similar questions as for expanding T-cells. For instance, where are expanding B-cells located, how do they interact with expanding T-cells, and do they perhaps even recognize the same tumor antigens. In EXPAND IT, we will use several innovative (single-cell) technologies to provide answers to these questions. These insights will much better characterize the mechanisms driving response to ICB, but will also provide important answers on how to sensitize patients not responding to ICB. Our findings could also contribute to the discovery of high-avidity anti-tumor TCRs that can be used in novel TCR-based cellular therapies.