Programmed Death 1 Expression on CD4 + T Cells Predicts Mortality after Allogeneic Stem Cell Transplantation

Abstract

Excessive or persistent programmed death 1 (PD-1) expression on virus- or tumor-specific T cells during chronic viral infection or malignancy has been associated with impaired immune control. To assess the role of the PD-1 pathway in allogeneic stem cell transplantation (SCT), we examined PD-1 expression and maturation phenotype on T cells from 42 patients early (day 55 to 85) after cord blood (CB), matched unrelated donor, and matched related donor transplantation. Expression of PD-1 on CD4 T cells was significantly elevated in all transplantation types, with the highest level observed in CB subjects. Elevated PD-1 expression on CD4 T cells early after transplantation was observed in nonsurvivors (median, 40.2%; range, 15.1 to 86.1) compared with survivors (median, 23.6%; range, 8.4 to 55.2; P = .001), indicating its association with increased risk for mortality, especially with CB transplantations, where PD-1 was increased in nonsurvivors (median, 64.6%; range, 36.5 to 86.1) compared with survivors (median, 34.1%; range, 15.9 to 55.2; P = .01). Furthermore, T cell subset analysis revealed that PD-1 expression was further elevated on CD4 T central memory in nonsurvivors (median, 49.8%; range, 15.1 to 83.4) compared with survivors (median, 24.8%; range, 8.9 to 71.3; P = .002) and on T effector memory cells in nonsurvivors (median, 69.1%; range, 24.7 to 92.6) compared with survivors (median, 43.7%; range, 13.9 to 96.5; P = .0003). Our findings suggest that elevation of PD-1 expression on CD4 T cells is associated with mortality in CB and possibly all SCT recipients.

PD-1 blockade for relapsed lymphoma post–allogeneic hematopoietic cell transplant: high response rate but frequent GVHD

“…It remains possible that anti-PD-1 administration during the earlier phase of transplantation would trigger severe GVHD secondary to decreased PD-1/PD-L1 ligation early post-allo-HCT. 48 Donor source, type of GVHD prophylaxis, history of GVHD, dose and timing of anti-PD-1 therapy, and immunosuppression at time of anti-PD-1 administration should be considered as variables potentially influencing the development of GVHD in clinical trials evaluating treatment with checkpoint blockade after allo-HCT.…”

Over-expression of PD-1 Does Not Predict Leukemic Relapse after Allogeneic Stem Cell Transplantation

“…This observation is consistent with the previous report of Gallez-Hawkins et al [14] demonstrating enhanced PD-1 expression during CMV reactivation and severe GVHD after allo-SCT. In another report, high PD-1 expression in CD4 cells was associated with non-survivors in allo-SCT of various stem cell sources [15]. Therefore, PD-1 blockade after allo-SCT may be a double-edged sword promoting antivirus immunity but inducing severe GVHD without increasing GVL effects.…”

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

“…As shown in a recent study, PD-1-expressing T-cells were increased early after transplantation and this was associated with worse survival. 63 We speculate that anti-PD-1 mAb's upregulate major histocompatibility antigens via activation of the interferon-g pathway, 2,21,64 decrease T regulatory cells, 65 and increase activated T and NK cells, thereby decreasing peripheral tolerance and increasing the incidence of GVHD. Well-designed correlative studies assessing T-cell subsets, PD-1/PD-L1 expression, and GVHD predictive markers before and after anti-PD-1 administration will be key to better understanding risks and identifying patients suitable to receive anti-PD-1 mAb's post-allo-HCT.…”