Germline Genetics in Immuno-oncology: From Genome-Wide to Targeted Biomarker Strategies

Abstract

In immuno-oncology (IO), the baseline host factors attract significant clinical interest as promising predictive biomarker candidates primarily due to the feasibility of noninvasive testing and the personalized potential of IO outcome prediction catered to individual patients. Growing evidence from experimental or population-based studies suggests that the host genetic factors contribute to the immunological status of a patient as it plays out at the multiple rate-limiting steps of the cancer immunity cycle. Recent observations suggest that germline genetics may be associated with tumor microenvironment phenotypes, autoimmune toxicities, and/or efficacy of immunotherapy regimens and overall cancer survival. Despite these highly intriguing indications, the potential of germline genetic factors as personalized biomarkers of immune-checkpoint inhibition (ICI) remains vastly unexplored. In this chapter, we review the rationale for exploring the germline genetic factors as novel biomarkers predictive of IO outcomes, including ICI efficacy, toxicity, or survival, and discuss the approaches for the identification of such germline genetic surrogates. Specifically, we focus on strategies for mapping the germline genetic biomarkers of ICI using genome-wide scans (genome-wide association analyses, next-generation sequencing technologies), followed by targeted assays, to be applied in clinical use. As we discuss the limitations, we highlight a need for large collaborative consortia in these efforts and sketch possible avenues for incorporating germline genetic factors into emerging multifactorial approaches for more personalized prediction of ICI outcomes.

Keywords: GWAS; Germline variants; Hereditability; Immune responsiveness; Immunotherapy; Next-generation sequencing; Targeted genotyping.