Journal
NATURE CANCER
Volume 2, Issue 9, Pages 950-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s43018-021-00226-4
Keywords
-
Categories
Funding
- European Research Council [648364]
- Hungarian Academy of Sciences [LP-2017-10/2017]
- National Research, Development and Innovation Office, Hungary [KKP-126506]
- EVOMER [GINOP-2.3.2-15-2016-00014]
- MolMedEx TUMORDNS [GINOP-2.3.2-15-2016-00020, GINOP-2.3.3-15-2016-00001, GINOP-2.3.2-15-2016-00026]
- 'Frontline' Research Excellence Program of the National Research, Development and Innovation Office, Hungary [KKP-129814]
- European Union [739593]
- New National Excellence Program of the Ministry of Human Capacities [UNKP-20-5]
- Bolyai Janos Research Fellowship of the Hungarian Academy of Sciences
- New National Excellence Program of the Ministry for Innovation and Technology [UNKP-20-2, UNKP-19-3, UNKP-20-4, UNKP-20-3]
- Szeged Scientists Academy under the sponsorship of the Hungarian Ministry of Innovation and Technology [FEIF/433-4/2020-ITM_SZERZ]
- European Research Council (ERC) [648364] Funding Source: European Research Council (ERC)
Ask authors/readers for more resources
The study found that cancer patients carrying HLA-I alleles with high peptide-binding promiscuity have significantly worse prognosis after immune checkpoint inhibition. This is due to the reduced capacity of the immune system to discriminate tumor neopeptides from self-peptides in such cases, leading to a shift in the regulation of tumor-infiltrating T cells.
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. Manczinger and colleagues define 'promiscuity' as a feature of HLA-I alleles representing peptide repertoire breadth; promiscuous alleles may promote a more tolerant tumor microenvironment and negatively impact tumor immune surveillance.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available