Abstract 603: Discovery of CD200R1 as a novel immuno-oncology target using pleiotropic signals from 23andMe’s genetic and health survey database

Abstract

Abstract Using large genetic and phenotypic datasets, 23andMe has developed a novel immuno-oncology target-identification platform. 23andMe has assembled a genetic database of nearly 12 million individuals, with 80 percent consented to research, coupled with health survey data comprising billions of responses. We identified hundreds of shared GWAS signals across phenotypes that appear to be driven by pleiotropic causal variants whose direction of effect (risk versus protection) systematically differs across cancer and autoimmune diseases including a signal linked to a clinically validated immune checkpoint receptor. This observation suggests that genes linked to such signals may be utilized by tumor cells to evade the immune system. We hypothesize that such signals indicate nodes of critical importance for anti-tumor immune response. By utilizing expression quantitative trait loci (eQTLs) and coding single nucleotide polymorphisms (SNPs) to link these signals to causal effects on genes, we identified CD200R1, an inhibitory receptor expressed on T cells and myeloid cells, as an immune checkpoint target. Immune-oncology associations were observed in multiple components of the CD200R1 pathway, including the receptor, its cognate ligand, CD200, and its downstream adaptor protein, DOK2. Expression of CD200R1 was validated in tumor-infiltrating lymphocytes using bulk and single-cell RNA-seq from various tumor types. This genetics-driven target discovery platform facilitated the development of a fully humanized monoclonal antibody that binds CD200R1 on immune cells with high affinity and enhances killing of tumor cells expressing CD200. [X. F. and W-J. C. contributed equally to this work.] Citation Format: Xin Fang, Wei-Jen Chung, Jill Fenaux, Alice Chen, Nizar Batada, Maike Schmidt, Sophia R. Majeed, Sushil Kumar, Steven Pitts. Discovery of CD200R1 as a novel immuno-oncology target using pleiotropic signals from 23andMe’s genetic and health survey database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 603.