Cancer immunotherapy has made great strides in recent years, yet improved approaches are required to achieve more durable responses in a greater number of patients. Blockade of the inhibitory receptor programmed-death 1 (PD-1) enables tumor-reactive T cells to effectively recognize and eliminate tumors in a subset of responsive patients, but many patients are resistant to PD-1 blockade. To improve response rates, we need to better understand the mechanisms that lead to therapeutic resistance. The overall goal of this project is to understand the role of T cell?intrinsic factors that contribute to patient response versus resistance to PD-1 blockade. We will identify signaling pathways and gene-expression patterns associated with blockade response with a particular focus on the role of T-cell receptor (TCR) affinity. We hypothesize that the make-up of TCR affinities of tumor-specific T cells affects tumor antigen recognition, activation signaling, and downstream gene expression, thus contributing to patient response to therapy. Analysis of these parameters in patient samples and mouse models of PD-1 blockade will allow us to identify T cell properties characteristic of response to therapy. In our first aim we will isolate and quantify the TCR-binding properties of melanoma antigen-specific T cells from PD-1 blockade?responsive and ?resistant patients to determine how TCR affinity profiles influence PD-1 blockade responses. In our second aim we will use proteomic and genomic analysis of patient antigen-specific T cells to develop a global signature of PD-1 blockade response and resistance. In our third aim we will use a panel of melanoma patient?derived TCRs with varying affinities for the same antigen for in vitro and in vivo experiments to determine how TCR affinity influences response to PD-1 blockade. Overall, we will determine the contribution of TCR affinities of melanoma-specific T cells to blockade resistance and will provide evidence to support the targeting of specific T cells based on TCR affinity for combination therapies and the selection of patients likely to respond to PD-1 blockade therapy based on TCR affinity profiles.
Blockade of the inhibitory checkpoint programmed-death 1 (PD-1) can be an effective immunotherapy for cancers, but many patients do not respond, and the mechanisms that drive resistance are not well understood. We will investigate how the intrinsic properties of tumor-specific T cells and the overarching influence of T cell receptor affinity determine T cell responsiveness to PD-1 blockade. This work has the potential to identify new strategies for overcoming therapeutic resistance to PD-1 blockade.
