Abstract
Patient genetic background contributed to antitumor immune responses at molecular and cellular levels.
Major Finding: Patient genetic background contributed to antitumor immune responses at molecular and cellular levels.
Concept: Tumor immune properties were found to be heritable and associated with germline SNPs in TCGA data.
Impact: This study creates a resource of variants that affect antitumor immunity and immunotherapy responses.
Although immunotherapy has become standard of care for many tumor types, a large proportion of patients do not respond, highlighting the need to better understand determinants of antitumor immune responses. To investigate the contributions of germline genetic variants to antitumor immunity, Sayaman, Saad, and colleagues analyzed data from more than 9,000 patients in The Cancer Genome Atlas (TCGA), in which an extensive set of tumor immune properties were assessed for heritability. Of these 139 previously defined traits, 10 immune traits were significantly heritable after correcting for multiple hypothesis testing, and 33 were nominally significant. The most heritable of these traits, with up to 15% to 20% heritability, included traits that clustered into modules involving T-cell subsets and IFN signatures. A subset of immune traits had heritability that interacted with defined immune subtypes. The heritability of some immune traits was higher in tumors that were of the wound healing subtype, and lower in the immune-active IFNγ-dominant or inflammatory subtypes. To investigate the impact of common germline genetic variants, genome-wide association studies of immune traits with at least nominally significant heritability were performed, identifying about 600 significant associations at 23 loci. Notably, three loci of interest, mapping to IFIH1, TMEM108, and STING1 (also known as TMEM173), were found to associate with IFN signaling traits, suggesting that these genes may modulate IFN response, a notion supported in part by in silico evaluation and previous literature. Candidates involved in differential immune infiltration were also identified and compiled into a comprehensive list; one such candidate was RBL1, a gene with homology to the tumor suppressor gene RB, which has been recently implicated in resistance to checkpoint inhibition. Lastly, rare cancer predisposition variants were analyzed, revealing associations between immune traits and mutations in BRCA1 and genes in telomere-stabilization and WNT–ß-catenin pathways. However, in patients with mutations of mismatch-repair genes, high leukocyte infiltration was dependent upon the acquisition of the microsatellite-unstable phenotype. Together, the results of this study provide a comprehensive analysis of patient germline genetic contributions to tumor immune properties and create a resource of candidate genes and variants that may modulate the antitumor immune response, which may one day aid in patient stratification for immunotherapy.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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