Dissecting temporal and spatial dynamics of immunotherapy resistance

PROJECT SUMMARY Immune checkpoint inhibitors (ICI) are now used as first line therapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), yet, only one out of six patients respond. How the composition and spatial organization of the tumor immune microenvironment relates to ICI efficacy in HNSCC is currently poorly understood. What is known, is that cancers are dynamic, evolving temporally and spatially in response to therapeutic pressures, with building support suggesting that on treatment assessment is more predictive of ICI response than assessment of pre-treatment tissue. In this proposal we will apply innovative single cell sequencing and imaging approaches to answer a critical question impeding progress in head and neck cancer care: how the spatial and temporal evolution of tumor and immune cells impacts ICI resistance. Aim 1 will distinguish tumor cell programs that associate with ICI resistance in primary tissue and serially measure alterations in these genes in circulating tumor cells. Aim 2 will define how T and B cell subpopulations and spatial architecture change with ICI initiation and how alterations relate to ICI resistance. Completion of these mentored aims will set the stage for the long term goal of developing improved predictive biomarkers of ICI response and identifying new targets for combinatorial therapies. This career development proposal presents a five-year plan to both accomplish the outlined scientific aims as well as a detailed training program to ensure the candidate’s transition to research independence. The candidate is an Instructor in Otolaryngology-Head and Neck Surgery at Harvard Medical School, Massachusetts Eye and Ear and Massachusetts General Hospital. The training aims, which include hand on experience, coursework and seminars focused on immunogenomics, build on the candidate’s previous research experience in cancer genomics and clinical experience as a head and neck cancer surgeon. Mentorship will be provided by thought leaders in single cell imaging and sequencing, bioinformatics, biomarker science, and cancer immunology including the primary mentorship team of Dr. Shannon Stott, PhD, Keith Flaherty, MD and Nir Hacohen, PhD at Massachusetts General Hospital Cancer Center.