The therapeutic potential of allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for the cure of malignant disease relies on cellular immunotherapy mediated by donor T lymphocytes infused with the graft or as donor lymphocyte infusions. Graft versus Tumor (GvT) activity mediated by alloreactive donor T cells is being exploited in allogeneic HSCT also for the cure of advanced renal cell carcinoma, a cancer particularly sensitive to immune intervention. In these patients, partial and sometimes complete remissions have been observed after allogeneic HSCT, but they have been difficult to correlate with particular immune features. Since immunological tolerance plays an important role in the complex mechanisms underlying T cell-mediated GvT, the analysis of molecules involved in tolerance are of potential interest in order to improve our ability to predict which patients will benefit from allogeneic HSCT. Human Leukocyte Antigen (HLA)-G, a non-classical HLA molecule with immune-modulatory properties including a tolerogenic effect on T, NK and dendritic cells, is an interesting candidate to this regard. A 14 base pair (bp) insertion-deletion (ins-del) polymorphism in the 3'untranslated region of HLA-G has been shown to impact on HLA-G expression by alternative splicing and possibly transcriptional control by microRNAs. The 14bp-del allele has been shown to be associated with less tolerance and increased risk of acute graft versus host disease (GvHD) in HSCT from HLA-identical unrelated or HLA-identical sibling donors for beta-thalassemia (La Nasa G, et al., Br J Haematol 2007:139:284; Sizzano F, et al., Tissue Antigens 2012:79:326).
We have studied 51 allogeneic HSCT from HLA-identical sibling (n=43) or matched unrelated (n=8) donors performed between 1995 and 2006, for patients affected by advanced stage renal carcinoma at the Centers of Milan, Marseille, Clermont-Ferrand and Stockholm. The HLA-G 14bp-ins/del polymorphism, typed by sequence-specific priming, was found to be identical for patient and donor in 27 pairs, and was therefore typed from patient cells only in the 24 additional transplants. Transplant conditioning was fludarabine-based in all cases. GvHD prophylaxis consisted in cyclosporine ± ATG. At a median follow-up time of 66 (36–100) months, 6/51 of patients are alive with a median overall survival (OS) of 10 months and an estimated 5-year OS of 13%. No clear correlation was found between HLA-G 14bp-ins/del polymorphism and GVHD, as 10/10 (100%) patients with the 14bp-del/del genotype experienced aGvHD grade 2–4, compared to 26/31 (83.9%) with at least one 14bp-ins allele (p=NS). In contrast, multivariate analysis adjusted for patient age and donor type showed that the probability of survival was markedly higher after transplant in patients homozygous for the 14bp-del/del genotype, compared to those homozygous for the 14bp-ins/ins genotype (HR 2.384; 95% CI0.956–5.947; p=0.062).
Taken together, these data suggest an association between the HLA-G 14bp del/del genotype and improved OS after allogeneic HSCT for renal cell cancer, possibly through T cell-mediated GvT in the presence of lower immunological tolerance associated with this genotype.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.