Epigenetic and Spatial Single-cell profiling in the context of Cancer Immunotherapy

Cancer immunotherapy using immune-checkpoint blockade (ICB) has created a paradigm shift in the treatment of advanced-stage cancers. One of the major limitations of ICB, however, is that it provides durable clinical responses only in a small fraction of patients. Moreover, to date, there is no reliable method to predict which patients will respond to ICB. Finally, many combined ICB therapies are currently being tested in numerous clinical trials that often lack a sound scientific rationale. With this project, we aim to discover why immunotherapy is effective in some patients but not in others by gaining novel insights into the cellular and molecular mechanisms underlying intrinsic resistance to ICB. To this end, we will serially collect pre- and on-treatment biopsies from advanced head and neck squamous cell carcinoma patients and establish dynamic maps of the entire tumor ecosystem before and during ICB using innovative and integrative single-cell profiling methods. We will integrate single-cell transcriptomic, epigenomic, and proteomic datasets with spatial data in order to monitor the therapeutic response to ICB at an unprecedented resolution. We expect that these dynamic spatiotemporal single-cell maps will help identify composite biomarkers that predict response to ICB and reveal novel treatment combinations that will ultimately provide long-term therapeutic responses in refractory patients.