Cancer immunotherapy is only highly effective in a small fraction of patients. Lim et al. now show that across all cancers there is an association between germline genetic variants and the immune features of the tumour, and that genetic background might affect responses to immunotherapy.

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Expression quantitative trait loci (eQTL) are genomic loci that harbour polymorphisms that are associated with gene transcript levels (eGenes). Lim et al. started their analysis by identifying eQTL–eGene pairs in each of the 24 cancer types present in The Cancer Genome Atlas (TCGA) database. After correcting for copy number alterations, which are acquired by the tumours rather than inherited, this resulted in a list of genes under germline genetic control for each tumour. The majority of these eGenes were tumour-specific; however, for each cancer type, gene ontology showed an enrichment of multiple immune-related gene sets. This suggests a germline influence on antitumour immune responses.

The authors investigated further the potential impact of germline variants on immunotherapy response. They selected eGenes under strong germline genetic control by filtering those eQTL–eGene pairs for which the genetic variants could account for most of the eGene expression variance. Of these eGenes, they focused on ERAP2, a gene involved in antigen processing. Analysis of the RNA sequencing data from a phase II clinical trial of anti-programmed cell death 1 ligand 1 (PDL1) in urothelial bladder cancer showed that ERAP2 expression was significantly associated with patients’ overall survival. Unfortunately, no genetic data were available for this trial and, therefore, the association of the relative eQTL with survival could not be confirmed. Nonetheless, these data support a role for inherited genetic variants in determining immunotherapy efficacy.

Finally, the authors tested whether germline genetics influences immune cell infiltration by checking the association of genetic polymorphisms with gene signatures of several lymphoid and myeloid immune cell types. They found several gene signature QTLs (gsQTLs), many of which were significantly associated with multiple immune cell gene signatures, suggesting a widespread effect of germline genetics on immune infiltration within the tumour microenvironment.

These findings show that the immunological properties of a tumour are not only determined by the acquired genetic features of the tumour itself but also by the genomic background of the host, and that these genetic variants may play a major part in shaping individual antitumour immune responses.