Deciphering Patient Specific Inter and Intra-Tumor Heterogeneities in Head and Neck Squamous Cell Carcinomas (HNSCC) for Optimized Radiation Therapy.
2Department of Oral and Maxillofacial Surgery, Hadassah Medical Center, Israel
HNSCC is the sixth leading cancer worldwide with 5-year survival rate. Targeted therapy, including immune modulating treatments, radiotherapy (RT) and surgery, are common in treating advanced stages, but have shown no significant responses. Inter and intra-tumor heterogeneities are of the main reasons for treatment resistance which compromise treatment outcome. Our goal is to characterize patient specific changes in intra-tumor heterogeneity of protein expression levels following RT and to sensitize tumors to our predicted targeted treatment.
To resolve cellular heterogeneity, we developed an information-theoretic single-cell quantification strategy which uses single cell protein expression levels and computes a cell specific barcode (CSB) for every tumor cell. A CSB reflects a set of ongoing processes in each cell. Cells with identical barcodes are grouped to represent different subpopulations. Molecular processes in each subpopulation are further examined to assign targeted drug combinations to enhance tumor response to RT. We validate this concept using patient-derived (PDX) oral cancer tissues which change intra-cellular phenotypes in response to RT.
PDX tissues show different subpopulations that expanded in response to RT. For example, in certain tissue, a significant expansion of two distinct subpopulations - one was PDL1 positive, and another harbored induced and co-expressed EGFR/HER2 proteins - was observed. These results suggest that a tumor response to RT can be enhanced through simultaneous inhibition of those subpopulations.
We suggest that an accurate resolution of HNSCC intra-tumor heterogeneity will allow us to provide an essential step towards the accurate design of targeted drug combinations to overcome tumor resistance.