Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy. The contribution of genetic factors to the tumour immune microenvironment (TIME) remains to be investigated. Here, the authors suggest the role of TIME eQTLs for target genes involved in reversing immune suppressive features.

Automated summary

Understanding how host genetics affects the tumor immune microenvironment (TIME) is essential for personalized cancer screening and treatment strategies. A study analyzed the eQTLs affecting TIME and found that they are enriched in areas of active transcription and associated with gene expression in specific immune cell subsets. Polygenic score models built with TIME eQTLs can stratify cancer risk, survival, and immune checkpoint blockade (ICB) response. Inhibiting the CTSS gene, which is implicated by the polygenic models, slows tumor growth and extends survival, suggesting the potential of integrating genetic factors and TIME characteristics for immunotherapy targets.