Research of the Freed-Pastor Lab
Dissecting the mechanisms of immune evasion in pancreatic cancer
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Despite considerable progress in understanding the molecular basis of this disease, pancreatic cancer continues to carry a dismal prognosis with fewer than 10% of patients surviving to five years. Decades of work has proven that the human immune system has the ability to recognize cancer as foreign, in a similar way to a virus or bacteria. However, cancers often acquire ways to “hide” from the immune system in order to avoid being killed. Insights into the mechanisms by which certain tumors “hide” from the immune system have fueled tremendous clinical successes in a range of tumor types. Unfortunately, the vast majority of pancreatic cancer patients have failed to benefit from current immune-based therapies. We use advanced preclinical modeling (organoids and mouse models) to investigate how pancreatic cancer escapes immune attack.
The Freed-Pastor laboratory has been at the forefront of characterizing the antigen landscape of pancreatic cancer and using these insights to develop novel therapeutic strategies. While computational predictions are often used as a proxy to nominate putative neoantigens, empiric detection using mass spectrometry-based immunopeptidomics provides direct evidence of peptide presentation in the context of human leukocyte antigen class I (HLA-I). Emerging evidence has demonstrated that cancer cells translate regions of the “dark” genome (i.e., the ostensibly non-coding genome), which generates cryptic (non-canonical) peptides capable of presentation by HLA-I. Using high-resolution immunopeptidomics, we recently discovered that cryptic peptides are abundant in the pancreatic cancer immunopeptidome. Using a highly sensitive ex vivo platform for priming and expansion of antigen-specific T cells we have identified and characterized numerous cryptic antigen-specific T cell receptors (TCRs), as well as neoantigen-specific TCRs targeting somatic mutations. TCR-redirected T (TCR-T) cells are generated prior to functional evaluation against patient-derived organoids and patient-derived xenograft models.
In addition, we recently developed preclinical models of “immunogenic” pancreatic cancer which facilitate the study of the interplay between a developing pancreatic tumor and the immune system with unprecedented detail. Using these mouse models, we have already uncovered a combination of three immunotherapy drugs (TIGIT/PD-1 co-blockade plus CD40 agonism; TIGIT/PD-1CD40a) that leads to profound responses in our preclinical models, now being evaluated as part of an early-phase clinical trial.
The Freed-Pastor laboratory also leverages cutting-edge CRISPR technologies (CRISPR-activation, -inhibition, -knockout, prime-editing) to perform in vivo gene perturbation studies and functionally interrogate putative mechanisms of PDAC immune evasion.
