Sidharth V. Puram, MD, PhD, Technology Impact Award Recipient Washington University School of Medicine Area of Research: Head and Neck Cancer Despite immunotherapy’s progress, mechanisms of resistance can dampen the effect of immune checkpoint therapy and diminish patient responses to treatment. Thus, resistance represents a persistent challenge in the care of cancer patients, with numerous outstanding questions about immunotherapy resistance. For example, it is unclear whether resistance is due to a few tumor cells in a unique cell state prior to treatment that allows them to escape destruction, or if instead it is the result of a slower evolution of resistance (i.e. an adaptive response). To answer such questions, Dr. Puram and his team have developed single-cell “Calling Cards”, a technology that acts as a novel molecular memory system. This method allows for analysis of each individual cell separately, and also enables “recording” of the key changes in cells as they acquire resistance. Specifically, he will be able to record changes in gene expression within the cells. Importantly, changes can be recorded in a cell at multiple time points, allowing for correlation with the cell’s behavior at different time points — almost like a time machine that will enable determination of what early changes might have occurred in cells that were ultimately resistant to treatment. He aims to use this technology to “go back in time” and determine which cell states enable head and neck squamous cell carcinoma (HNSCC) cells to become resistant to immunotherapy. This will allow direct testing of the hypothesis that there are subpopulations of tumor cells in pre-existing cell states that provide resistance to immunotherapy and identify genes/pathways that could be targeted by new therapeutics or serve as biomarkers to predict which patients will ultimately respond to treatment. The methods he seeks to develop will be immediately applicable to similar problems across oncology and even other diverse biological settings, enabling early adoption by the research community at large. Furthermore, the genes and pathways identified are likely to be conserved in multiple cancer types, creating opportunities for pan-cancer drugs and biomarkers that will meaningfully affect patient care and outcomes. Projects and Grants An inducible molecular memory system to unravel the mechanisms of immunotherapy resistance in oncology Washington University School of Medicine | Head and Neck Cancer | 2021
