Effects of genetic polymorphism in MHC, KIR, and related loci on human disease

Division Of Basic Sciences - Nci

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Abstract

Immune checkpoint inhibition therapy (ICI) is now first-line therapy for certain cancers, but response rates rarely exceed 40% and side effects of these drugs can be debilitating and even lethal. There is a critical need for improved predictive biomarkers to facilitate better patient stratification and management algorithms. We measured the effect of HLA variation on survival in patients with advanced cancer treated with various ICI vs. alternative therapies and found that HLA-A*03 was associated with shorter survival in each tumor type evaluated in these analyses. Overall responses to ICI were absent or rare in HLA-A 03 homozygotes. Thus, HLA-A 03 is a predictive biomarker of poor response to ICI and should be considered in decisions regarding cancer therapy. We are interested in determining the basis for the deleterious effect of HLA-A 03 in patients treated with ICI and identifying additional immunogenetic risk factors (or beneficial variants) in cancer and cancer immunotherapy. HLA-I allotypes vary widely in their dependence on tapasin (TAPBP), an integral component of the peptide loading complex, to present peptides on the cell surface. We have determined tapasin dependence (TD) values for common HLA-I allotypes across worldwide populations (N = 250), which show a continuum of values for HLA-A, HLA-B and HLA-C. This variation is functionally relevant, as tapasin-independent allotypes were shown to present a broader array of peptides than tapasin-dependent allotypes, and tapasin independence conferred protection in HIV-1 disease. Given the role of tapasin in shaping the HLA-I peptide repertoire and its impact on disease outcome, we hypothesized that natural variation in its expression level could also affect disease pathogenesis and susceptibility. We identified two single nucleotide polymorphisms (SNPs) that control TAPBP mRNA expression, and those that confer higher TAPBP expression associate with protection against malaria outcomes specifically amongst individuals with tapasin-dependent HLA allotypes. Tapasin expression had no effect on tapasin-independent allotypes. These data highlight the importance of cellular immunity against malaria at the liver stage of disease. Long-term persistence of Ebola virus (EBOV) in immunologically privileged sites has been implicated in recent outbreaks of Ebola virus disease (EVD) in Guinea and the Democratic Republic of Congo. We collaborated on a study with investigators at the CDC to try to understand how the acute course of EVD, convalescence, and host immune and genetic factors may play a role in prolonged viral persistence in semen. A cohort of 131 male EVD survivors in Liberia were enrolled in a case-case study. "Early clearers" were defined as those with 2 consecutive negative EBOV semen test results by real-time reverse-transcription polymerase chain reaction (rRT-PCR) greater than or equal to weeks apart within 1 year after discharge from the Ebola treatment unit or acute EVD. "Late clearers" had detectable EBOV RNA by rRT-PCR greater than 1 year after discharge from the Ebola treatment unit or acute EVD. Compared with early clearers, late clearers were older (median, 42.5 years) and experienced fewer severe clinical symptoms. Late clearers had more lens opacifications, after accounting for age, higher total serum immunoglobulin G3 (IgG3) titers, and increased frequency of HLA-C 0304. Overall, older age, decreased illness severity, elevated total serum IgG3 and HLA-C 0304 allele expression may be risk factors for the persistence of EBOV in the semen of EVD survivors. EBOV persistence in semen may also be associated with its persistence in other immunologically protected sites, such as the eye.