PD-1 and CTLA-4 up regulation on donor T cells is insufficient to prevent GvHD in allo-HSCT recipients

Abstract

The expression of checkpoint blockade molecules PD-1, PD-L1, CTLA-4, and foxp3+CD25+CD4+ T cells (Tregs) regulate donor T cell activation and graft-vs-host disease (GvHD) in allogeneic hematopoietic stem cell transplant (allo-HSCT). Detailed kinetics of PD-1-, CTLA-4-, and PD-L1 expression on donor and host cells in GvHD target organs have not been well studied. Using an established GvHD model of allo-HSCT (B6 → CB6F1), we noted transient increases of PD-1- and CTLA-4-expressing donor CD4+ and CD8+ T cells on day 10 post transplant in spleens of allo-HSCT recipients compared with syngeneic HSCT (syn-HSCT) recipients. In contrast, expression of PD-1- and CTLA-4 on donor T cells was persistently increased in bone marrow (BM) of allo-HSCT recipients compared with syn-HSCT recipients. Similar differential patterns of donor T cell immune response were observed in a minor histocompatibility (miHA) mismatched transplant model of GvHD. Despite higher PD-1 and CTLA-4 expression in BM, numbers of foxp3+ T cells and Tregs were much lower in allo-HSCT recipients compared with syn-HSCT recipients. PD-L1-expressing host cells were markedly decreased concomitant with elimination of residual host hematopoietic elements in spleens of allo-HSCT recipients. Allo-HSCT recipients lacking PD-L1 rapidly developed increased serum inflammatory cytokines and lethal acute GvHD compared with wild-type (WT) B6 allo-HSCT recipients. These data suggest that increased expression of checkpoint blockade molecules PD-1 and CTLA-4 on donor T cells is not sufficient to prevent GvHD, and that cooperation between checkpoint blockade signaling by host cells and donor Tregs is necessary to limit GvHD in allo-HSCT recipients.

Reversal of T Cell Exhaustion by the First Donor Lymphocyte Infusion Is Associated with the Persistently Effective Antileukemic Responses in Patients with Relapsed AML after Allo-HSCT

“…In addition, both of the studies mentioned were performed in small cohorts without case-paired nonrelapsed control subjects. As reported previously by us and other researchers, CMV reactivation, especially refractory infection significantly influenced PD-1 expression on T cells [27,36], post-transplant time, and GVHD also have an impact on PD-1 expression on T cells [27,28]. Besides, patients receiving ATG-based conditioning regimen showed significantly different T cell differentiation pattern with significantly lower percentages of CD45RA + T cells, but higher percentages of CD45RO + T cells, especially within 180 days after allo-HSCT compared with those patients who did not [25].…”

“…Tim-3 expression and coexpression of PD-1 and Tim-3 on T cells did not significantly change ( Figure 1A,B). In addition, GVHD was demonstrated to be associated with increased PD-1 expression after allo-HSCT [27,28]. To evaluate the GVHD impact on PD-1 and Tim-3 expression on T cells, a 1:2 ratio of cases and control subjects were selected from the relapsed and nonrelapsed groups, respectively, and matched by posttransplant time.…”

Recommendations for managing PD-1 blockade in the context of allogeneic HCT in Hodgkin lymphoma: taming a necessary evil

“…In some murine models, checkpoint blockade administered before and within days after transplant was shown to accelerate GVHD lethality. 20,21,62 Thus, it remains possible that administration during the earlier phase of transplantation…”

Immune checkpoint inhibitors in the management of malignancies in transplant recipients

“…However, the rate and extent of GVHD in patients who were treated with immune checkpoint inhibitors has been shown to be reduced by using cyclophosphamide as prophylaxis 43. Moreover, PD-L1 expression on haematopoietic cells might reduce the chance of developing GVHD analogous to PD-L1 expression pattern on kidney tubular epithelium 44. Finally, the risk of misclassification due to the clinical and histopathological similarity between checkpoint blockade therapy toxicity and GVHD should be carefully considered 45…”