부산대학교 도서관

Priming the immune system by blockade of immune checkpoint proteins has revolutionized cancer therapy and achieved durable clinical responses. Despite the success of targeting the PD1-PDL1 axis or CTLA-4 to release the breaks on T cells, the response across cancer types and patients has not been uniform. One of the reasons is the heterogenous immune evasion mechanisms displayed by the tumour. With over forty immune checkpoint proteins identified, there remains much to understand regarding the underlying biology. Insights into the specific regulation of surface expression of immune receptors may aid in developing rational immunotherapeutic strategies. This thesis describes the use of a haploid genetic screening approach to uncover regulatory mechanisms of several immune checkpoint proteins expressed on cancer cells. First, we investigate which endogenously expressed immune checkpoint proteins can be interrogated in the human haploid cell line HAP1 and subsequently focus on Polio Virus Receptor (PVR), B7 homolog 3 (B7H3) and Neuropilin-1 (NRP1) (Chapter 2). Chapters 2 and 3 concern the genetic screens on B7H3, PVR and NRP1, and initial validation of newly identified regulators. In Chapter 4, we report the identification of UBE3D as a novel regulator of the immune checkpoint and angiogenesis-associated protein, NRP1. Our data provide a potential mechanistic basis for a risk association between an inherited variant of UBE3D and age-related macular degeneration (AMD). Specifically, UBE3D loss of function resulted in reduced lysosomal degradation of NRP1 and increased angiogenesis in a zebra fish model.