William Freed-Pastor

Our laboratory is focused on dissecting the mechanisms of immune escape and tumor-immune crosstalk in pancreatic cancer and other malignancies, with the overarching goal of rapidly using these insights to guide therapeutic advances for cancer patients. Utilizing high-resolution immunopeptidomics on patient-derived organoids and primary tumors, we have conducted extensive antigen discovery work in pancreatic cancer in recent years. This work uncovered aberrant translation of the putatively non-coding genome (“dark proteome”) as a novel source for shared cancer-restricted HLA-I bound peptides capable of recognition by cytotoxic T lymphocytes. In addition, we established a T cell receptor (TCR) discovery and validation pipeline in which engineered TCR-T cells are functionally vetted for activity against patient-derived organoids. We have successfully used this platform to identify numerous neoantigen- or cryptic antigen-specific TCRs, and ongoing efforts are aimed at expanding this platform to accelerate effective cellular therapies in pancreatic cancer. Moreover, our laboratory has developed sophisticated preclinical mouse models to enable functional dissection of immune evasion in pancreatic cancer through in vivo CRISPR-based genetic engineering. We are currently leveraging these models to functionally interrogate putative mechanisms of immune evasion and T cell dyslocalization, as well as preclinically evaluating combination immune-based therapeutic strategies in pancreatic cancer. The current major focus of our laboratory thus involves understanding the optimal antigen sources for effective T cell-based therapies in pancreatic cancer and other malignancies and utilizing these insights to develop novel therapeutics. We are also deeply involved in immuno-oncology clinical trials at Dana-Farber Cancer Institute to accelerate the development of effective immune-based therapies for pancreatic cancer.