Human leukocyte antigen-G donor-recipient matching of the 14-base pair polymorphism protects against cancer after heart transplant

Mitchell B Adamson; Roberto V P Ribeiro; Frank Yu; Julieta Lazarte; Kyle Runeckles; Cedric Manlhiot; Vivek Rao; Diego H Delgado

doi:10.1016/j.healun.2020.03.024

Human leukocyte antigen-G donor-recipient matching of the 14-base pair polymorphism protects against cancer after heart transplant

J Heart Lung Transplant. 2020 Jul;39(7):686-694. doi: 10.1016/j.healun.2020.03.024. Epub 2020 Apr 7.

Authors

Mitchell B Adamson¹, Roberto V P Ribeiro¹, Frank Yu², Julieta Lazarte², Kyle Runeckles³, Cedric Manlhiot⁴, Vivek Rao¹, Diego H Delgado⁵

Affiliations

¹ Peter Munk Cardiac Center, University Health Network, Toronto, Ontario, Canada; Faculty of Medicine, Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
² Peter Munk Cardiac Center, University Health Network, Toronto, Ontario, Canada.
³ The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴ Peter Munk Cardiac Center, University Health Network, Toronto, Ontario, Canada; The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Peter Munk Cardiac Center, University Health Network, Toronto, Ontario, Canada. Electronic address: diego.delgado@uhn.ca.

PMID: 32317137
DOI: 10.1016/j.healun.2020.03.024

Abstract

Background: After a transplant, cancer is a leading cause of morbidity and mortality. Human leukocyte antigen-G (HLA-G)-an immune checkpoint molecule-reduces allograft rejection by dampening host immune responses. Reports suggest malignant cells utilize HLA-G to evade the immune system and promote cancer development. Our objective was to evaluate HLA-G donor-recipient polymorphism matching and development of cancer after a heart transplant.

Methods: Recipients (n = 251) and corresponding donors (n = 196) were genotyped retrospectively to identify HLA-G polymorphisms in the 5' regulatory (-725, -201), 3' untranslated (+3,197, +3,187, +3,142, 14-base pair insertion-deletion polymorphism [14-bp indel]) and coding regions (Haplotypes I-VI). Associations between donor-recipient polymorphism matching and development of cancer were assessed through multivariate proportional hazard regression models.

Results: Recipient and donor (48.2 ± 12.1 and 35.5 ± 14.3 years, respectively) mean follow-up was 7.2 ± 4.6 years. Overall, 42 (16.7%) recipients developed de novo post-transplant cancer. 14-bp polymorphism matching significantly reduced the proportion of cancer, revealing an independent protective effect (hazard ratio [95% CI]: 0.26 [0.10-0.75]; p = 0.012). Recipients with the 14-bp insertion sequence, whether homozygous or heterozygous, had a lower proportion of cancer (p > 0.008), matching the INS sequence (INS/INS and INS/DEL) protected against cancer (p = 0.002). No differences were seen between matched vs unmatched cohorts regarding all donor-recipient pre-transplant and post-transplant characteristics. No other polymorphisms showed significant associations.

Conclusions: We investigated donor-recipient HLA-G polymorphism matching and development of cancer following a heart transplant. Donor-recipient 14-bp matching was an independent protective factor against cancer development. HLA-G may have a role in therapeutic and diagnostic strategies against cancer. Identifying relevant HLA-G polymorphisms may warrant alterations in immunotherapy to reduce post-transplant cancer risk.

Keywords: HLA-G; cancer; heart transplantation; human leukocyte antigen; immune checkpoint; polymorphism; tolerance.

MeSH terms

Base Pairing / genetics
DNA, Neoplasm / genetics*
Female
Follow-Up Studies
Genotype
Graft Rejection / genetics*
Graft Rejection / immunology
Graft Survival
HLA Antigens / genetics*
HLA Antigens / metabolism
Heart Transplantation / adverse effects*
Humans
Male
Middle Aged
Neoplasms / etiology*
Neoplasms / immunology
Polymorphism, Single Nucleotide*
Retrospective Studies
Tissue Donors

Substances

DNA, Neoplasm
HLA Antigens