PD-1 genotype of the donor is associated with acute graft-versus-host disease after HLA-identical sibling donor stem cell transplantation

Abstract

Programmed death 1 (PD-1) activation triggers an immune checkpoint resulting in inhibition of T cells that leads to peripheral tolerance. Some PD-1 polymorphisms have been described and associated with the development of autoimmune diseases or cancer predisposition, but there are few data concerning the relevance of such polymorphisms on the clinical outcome after allogeneic hematopoietic stem cell transplant (alloHSCT). We analyzed the distribution of the SNPs PD-1.1G/A (rs36084323) and PD-1.3G/A (rs11568821) genotypes of the donor in a cohort of 1485 alloHSCT from HLA-identical sibling donors. We found an increased risk of grades II to IV graft-versus-host disease (GvHD) in patients receiving grafts from donors homozygous for the G allele at the rs36084323 SNP (P = 0.033; hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.1 to 4.8) and also from donors homozygous for the A allele at the rs11568821 position (P < 0.001; HR 4.5, 95%CI 2.0 to 10.1). In contrast, the PD-1 genotype of the donor did not show association with overall survival or relapse incidence. These results suggest that the PD-1 genotype of the donor plays an important role for the development of acute GvHD after alloHSCT from HLA-identical sibling donors.

Preexisting Autoimmune Disease: Implications for Immune Checkpoint Inhibitor Therapy in Solid Tumors

“…[15][16][17][18][19] Similarly, certain polymorphisms in PD-1 have been associated with increased risk of acute GVHD and RA. 20,21 DNA methylation of genes involved in PD-1/ PD-L1 expression and the interferon-gamma pathway have also been implicated in both ICI response and susceptibility to SLE. [22][23][24] It has also been noted that CTLA-4 is expressed on some normal tissues, such as the pituitary gland, and that direct binding of the ICI to this receptor followed by a complement-mediated immune response may also result in organ-specific toxicity.…”

Genetic variants of CTLA4 are associated with clinical outcome of patients with multiple myeloma

“…Several studies have shown a relationship between genetic polymorphisms in costimulatory/inhibitory molecules and susceptibility to the development of hematologic malignancies, such as non-Hodgkin lymphomas (9, 10), chronic lymphocytic leukemia (11,12), and MM (13)(14)(15)(16)(17). In addition, some studies have described the correlation between CTLA4 and PDCD1 genotypes and the clinical outcome after allogeneic stem cell transplantation (18, 19) or with the risk of acute myeloid leukemia progression after achieving complete remission (20).…”

Analysis of Relationships between Immune Checkpoint and Methylase Gene Polymorphisms and Outcomes after Unrelated Bone Marrow Transplantation

“…Blockade of the PD-1/PD-L pathway has been shown to enhance aGVHD lethality in mice [ 45 ]. In a Spanish study, two PD-1 SNPs in donors were associated with grade 2–4 aGVHD in HLA-identical sibling HSCT [ 34 ]. In the present study, another PD-1 SNP, rs2227982, was not associated with any post-uBMT outcomes.…”

“…To the best of our knowledge, while many candidate SNP studies have investigated the relationship between CTLA4 and post-HSCT outcomes in humans [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ], no or only a few candidate SNP studies have been published on the relationship between PD1 [ 34 ], BTLA , LAG3 , DNMT1 , and EZH2 and post-HSCT outcomes in humans.…”