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Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.

Summary: Humans exhibit considerable variability in their immune responses to the same immune challenges. Such variation is widespread and affects individual and population‐level susceptibility to infectious diseases and immune disorders. Although the factors influencing immune response diversity are partially understood, what mechanisms lead to the wide range of immune traits in healthy individuals remain largely unexplained. Here, we discuss the role that natural selection has played in driving phenotypic differences in immune responses across populations and present‐day susceptibility to immune‐related disorders. Further, we touch on future directions in the field of immunogenomics, highlighting the value of expanding this work to human populations globally, the utility of modeling the immune response as a dynamic process, and the importance of considering the potential polygenic nature of natural selection. Identifying loci acted upon by evolution may further pinpoint variants critically involved in disease etiology, and designing studies to capture these effects will enrich our understanding of the genetic contributions to immunity and immune dysregulation. [ABSTRACT FROM AUTHOR]

Only a third of immune-associated loci from genome-wide association studies (GWAS) colocalize with expression quantitative trait loci (eQTLs). To learn about causal genes and mechanisms at the remaining loci, we created a unified single-cell chromatin accessibility (scATAC-seq) map in peripheral blood comprising a total of 282,424 cells from 48 individuals. Clustering and topic modeling of scATAC data identified discrete cell-types and continuous cell states, which helped reveal disease-relevant cellular contexts, and allowed mapping of genetic effects on chromatin accessibility across these contexts. We identified 37,390 chromatin accessibility QTLs (caQTL) at 10% FDR across eight cell groups and observed extensive sharing of caQTLs across immune cell contexts, finding that fewer than 20% of caQTLs are specific to a single cell type. Notably, caQTLs colocalized with ∼50% more GWAS loci compared to eQTLs, helping to nominate putative causal genes for many unexplained loci. However, most GWAS-caQTL colocalizations had no detectable downstream regulatory effects on gene expression levels in the same cell type. We find evidence that the higher rates of colocalization between caQTLs and GWAS signals reflect missing disease-relevant cellular contexts among existing eQTL studies. Thus, there remains a pressing need for identifying disease-causing cellular contexts and for mapping gene regulatory variation in these cells.

Genome-wide association studies performed in patients with coronavirus disease 2019 (COVID-19) have uncovered various loci significantly associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity. However, the underlying cis -regulatory genetic factors that contribute to heterogeneity in the response to SARS-CoV-2 infection and their impact on clinical phenotypes remain enigmatic. Here, we used single-cell RNA-sequencing to quantify genetic contributions to cis -regulatory variation in 361,119 peripheral blood mononuclear cells across 63 COVID-19 patients during acute infection, 39 samples collected in the convalescent phase, and 106 healthy controls. Expression quantitative trait loci (eQTL) mapping across cell types within each disease state group revealed thousands of cis -associated variants, of which hundreds were detected exclusively in immune cells derived from acute COVID-19 patients. Patient-specific genetic effects dissipated as infection resolved, suggesting that distinct gene regulatory networks are at play in the active infection state. Further, 17.2% of tested loci demonstrated significant cell state interactions with genotype, with pathways related to interferon responses and oxidative phosphorylation showing pronounced cell state-dependent variation, predominantly in CD14 + monocytes. Overall, we estimate that 25.6% of tested genes exhibit gene-environment interaction effects, highlighting the importance of environmental modifiers in the transcriptional regulation of the immune response to SARS-CoV-2. Our findings underscore the importance of expanding the study of regulatory variation to relevant cell types and disease contexts and argue for the existence of extensive gene-environment effects among patients responding to an infection., Competing Interests: Disclosures/competing interests: J.B.R.’s institution has received investigator-initiated grant funding from Roche, Eli Lilly, GlaxoSmithKline, and Biogen for projects unrelated to this research. J.B.R. is the CEO of, and holds shares in, 5 Prime Sciences (www.5primesciences.com), which provides research services for biotech, pharma, and venture capital companies to enable genetics-based drug development.