Thinking Outside the Cancer Cell: Cancer Genomics for Immunotherapy 用癌細胞基因體學改善免疫療法

Abstract

Cancer immunotherapy has dramatically transformed the treatment landscape of advanced cancers. There are now seven FDA-approvedimmune checkpoint inhibitors targeting key immune checkpoint proteins, such as programmed death receptor-1 (PD-1), its ligand (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). For some patients, these agents extend lifespan and provide durable benefits. However, the majority of patients receiving these treatments do not benefit from them: response rates in clinical trials range from 10-50% and a fraction suffer from adverse immune toxicities. There is an urgent need for reliable predictors of immunotherapy response. Since the first report of cancer genome sequencing in 2006, we have gained a considerable understanding of the cell-autonomous effects—the effects induced upon cancer cells—caused by genomic alterations. Yet, how they affect the tumor microenvironment remains unclear. We studied the non-cell-autonomous effects, especially those affecting tumor-immune interactions, of the same cancer genomic alterations. The results highlight cancer predisposition and driver genes that may serve as biomarkers for prioritizing patient sub-populations for treatment. Notably, they also suggest response and resistance mechanisms that can be targeted to improve cancer immunotherapy.?