Dissecting Mechanisms of Immunotherapy Response in Patients with Melanoma - ¿
DESCRIPTION (provided by applicant): Incidence and death rates from melanoma are rising more rapidly than those of any other cancer. Tumors persist and metastasize despite a robust and specific immune response, including infiltration of cytotoxic T cells into the tumor. T cell behavior is tightly controlled by both co-stimulatory and inhibitory receptors. Many human tumors evade the immune response by co-opting these receptors, thus dampening the T cell response. A wave of novel therapies aimed at boosting the T cell response to cancer, whether through agonizing co-stimulatory receptors or antagonizing inhibitory receptors have recently been FDA approved or entered clinical trials. Specifically, novel therapy blocking the interaction between PD-1 and its ligands was approved for use in patients with advanced melanoma. It is thought that binding of programmed death-1 (PD-1), expressed on T cells, to its ligand within the tumor microenvironment dampens T cell-mediated killing. While a-PD-1 induces a clinical response in approximately 25% of advanced melanoma patients, the majority will ultimately relapse and die of their disease. The field remains hampered by an understanding of the effects of inhibitory receptor blockade on the systemic T cell populations. Additionally, no biomarker exists to predict which patients will benefit from a-PD-1 therapy. To dissect immune response to a-PD-1 therapy, this project utilizes high dimensional, single-cell technology to observe multiplexed phenotype and function of many immune cell subsets in patients with melanoma. The goal of this project is to dissect the phenotype, function, and signaling biology of T cells obtained from patients before, during, and after treatment in melanoma patients treated with recently approved anti-PD-1 therapy. T cells are a complex and heterogeneous subset of immune cells. Their state and capabilities can be characterized by a wide range of measurements, including surface marker expression, intracellular biochemical signaling, and ability to release cytotoxic moieties. Additionally, rare subsets within the T cell compartment, lie T regulatory cells, have a large impact on tumor biology. For these reasons, high dimensional, single-cell biology techniques are crucial for dissecting T cell phenotype and behavior. This project will utilize mass cytometry (CyTOF), a cutting edge technique capable of measuring expression of 35+ parameters simultaneously at the single cell level. Mass cytometry will be used to characterize the phenotype, dissect functional capabilities, and uncover signaling networks in both primary human melanoma tumors and sequential peripheral blood samples from melanoma patients treated with a-PD-1. This project will advance cancer research and patient care by identifying mechanisms by which T cells clear melanoma tumors during successful a-PD-1 therapy. Results from the anti-PD-1 therapy can be used to study and assess the success of other immunotherapies, both approved and in clinical trials. Sequential patient samples over the course of therapy will identify biomarkers of response and novel targets by which to further boost the immune response.
