Manczinger, Koncz, and Baogh et al. probed whether class I HLA-A, -B, and -C alleles, which bind a greater number of peptides (high promiscuity; Pr), and which are hypothesized to be important for a broader pathogen response, also impacted immune control by ICB. Calculating a Pr index for multiple abundant HLA alleles revealed a negative impact on clinical response for the mean Pr in a cohort of melanoma patients treated with anti-PD-1 axis therapy, and across untreated melanoma patients in TCGA. High Pr correlated with reduced ability to discriminate self- from neopeptides, and with multiple markers of immunosuppression and T cell dysfunction.
Contributed by Ed Fritsch
ABSTRACT: Human leukocyte antigen class I (HLA-I) genes shape our immune response against pathogens and cancer. Certain HLA-I variants can bind a wider range of peptides than others, a feature that could be favorable against a range of viral diseases. However, the implications of this phenomenon on cancer immune response are unknown. Here we quantified peptide repertoire breadth (or promiscuity) of a representative set of HLA-I alleles and found that patients with cancer who were carrying HLA-I alleles with high peptide-binding promiscuity have significantly worse prognosis after immune checkpoint inhibition. This can be explained by a reduced capacity of the immune system to discriminate tumor neopeptides from self-peptides when patients carry highly promiscuous HLA-I variants, shifting the regulation of tumor-infiltrating T cells from activation to tolerance. In summary, HLA-I peptide-binding specificity shapes neopeptide immunogenicity and the self-immunopeptidome repertoire in an antagonistic manner, and could underlie a negative trade-off between antitumor immunity and genetic susceptibility to viral infections.
Author Info: (1) Biological Research Centre, Institute of Biochemistry, Synthetic and Systems Biology Unit, Eötvös Loránd Research Network (ELKH), Szeged, Hungary. (2) Department of Dermatology
Author Info: (1) Biological Research Centre, Institute of Biochemistry, Synthetic and Systems Biology Unit, Eötvös Loránd Research Network (ELKH), Szeged, Hungary. (2) Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary. (3) MTA-SZTE Dermatological Research Group, Eötvös Loránd Research Network (ELKH), University of Szeged, Szeged, Hungary. (4) HCEMM-USZ Skin Research Group, Szeged, Hungary. (5) Szeged Scientist Academy, Szeged, Hungary. 6HCEMM-BRC Metabolic Systems Biology Lab, Szeged, Hungary. (7) These authors contributed equally: Máté Manczinger, Balázs Koncz,Gergő Mihály Balogh. e-mail: manczinger.mate@brc.hu; cpal@brc.hu
