부산대학교 도서관

Simple Summary: A major barrier to success for chimeric antigen receptor (CAR) T-cell therapies in solid tumors is selecting optimal target antigens. Target antigens should be uniformly expressed by cancer cells and minimally so by healthy tissues in the body. Analyzing single-cell RNA-sequencing data of patient tumors and of healthy tissue reference atlases, we first charted the landscape of existing solid tumor CAR targets, quantifying their tumor selectivity and safety to identify the leading clinical targets. We then compared these benchmark targets to the cell surfaceome, with the aim of systematically identifying new candidate genes that are safer and/or more selective than the best CAR targets in clinical trials, as determined by our measures. Our analysis uncovered twenty new cell surface targets, five of which have both superior selectivity and safety scores, which may serve as promising candidates for CAR treatments in HNSC. Chimeric antigen receptor (CAR) T cell therapies have yielded transformative clinical successes for patients with blood tumors, but their full potential remains to be unleashed against solid tumors. One challenge is finding selective targets, which we define intuitively to be cell surface proteins that are expressed widely by cancer cells but minimally by healthy cells in the tumor microenvironment and other normal tissues. Analyzing patient tumor single-cell transcriptomics data, we first defined and quantified selectivity and safety scores of existing CAR targets for indications in which they are in clinical trials or approved. We then sought new candidate cell surface CAR targets that have better selectivity and safety scores than those currently being tested. Remarkably, in almost all cancer types, we could not find such better targets, testifying to the near optimality of the current target space. However, in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSC), for which there is currently a dearth of existing CAR targets, we identified a total of twenty candidate novel CAR targets, five of which have both superior selectivity and safety scores. These newly identified cell surface targets lay a basis for future investigations that may lead to better CAR treatments in HNSC. [ABSTRACT FROM AUTHOR]