Pre-Clinical Studies

Evaluate the Immunogenic Effect of Heavy Particle Radiation

In vivo studies have shown that radiation therapy (RT) induces the release of damage-associated molecular patterns (e.g. HMGB1, calreticulin) into the extracellular matrix, spurring the recruitment and activation of antigen-presenting cells, which then prime cytotoxic T cells. Thus, RT works synergistically with immune activation mediating tumor death. Recent studies have confirmed that more HMGB1 is released with carbon ion RT than with gamma RT. In addition, evidence suggests increased clustered DNA damage producing higher levels of irreparable DNA fragments that elicits a higher innate immune response, upon reaching the cytosol, after carbon ion RT.

RT can potentially affect pancreatic cancer (PaCa), one the deadliest human cancer types,  as adjuvant treatment for chemo- and immunotherapy. However, PaCa cells use complex immune escape strategies to circumvent T-cell recognition, including activation/upregulation of immune checkpoint molecules, downregulation of classical MHC I expression, upregulation of HLA-E and HLA-G molecules, or intratumoral recruitment of T regulatory and myeloid-derived suppressor cells. Our ongoing research aims to determine whether carbon ion RT can initiate immune/inflammatory changes in human and murine PaCa cell lines that can specifically promote tumor sensitization.

We are also interested in studying the changes in tumor mutation burden (a measurement of induced neoantigens) in human and mouse PaCa cell lines mediated by carbon ion RT. Evaluating neoantigens can define potential new targets for immunotherapy (targeted antibody therapy, checkpoint inhibitors, vaccines) and identify tumor predictor markers for PaCa therapies. Our strategy to quantify the changes in RT-mediated neoantigens involves analyzing the whole exome sequence data and whole transcriptome (RNA-seq) data of each cell line before and after RT. Then, multiple in silico bioinformatics prediction algorithms are used to identify the kinetics/de novo generation of potential MHC-I restricted neoepitopes.