Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality

Abstract

Key Points PD-L1 and PD-L2 expression were upregulated during GVHD, whereas PD-1/PD-L1 was more critical than PD-1/PD-L2 in downregulating GVHD. Our data provide new insight into the differential roles of host PD-L1 and PD-L2 and associated mechanisms in controlling GVHD.

Nivolumab in a patient with refractory Hodgkin’s lymphoma after allogeneic stem cell transplantation

“…10,11 However, while it appears particularly appealing to reverse the suppression of allogeneic GVT effects with PD1 inhibition in the situation of HL relapse after alloSCT, special caution has to be taken in the context of an allogeneic immune system given the role of the PD1 axis in the pathophysiology of GVHD as well. 4 In the presented case of a patient with HL refractory to multiple lines of therapy including alloSCT and BV, nivolumab achieved a remarkable and fast response, suggesting PD1 inhibition to be a powerful means for unleashing the GVT effect in the immunosuppressive microenvironment of HL. However, we did not perform mechanistic studies and another potential cause might be a disruption of the HL supporting infiltrating leukocytes independent of a GVT effect.…”

“…Importantly, despite recent concerns, there were no signs of GVHD induction in our patient. While the mice in the study of Saha received PD1/PD-L1 inhibition from day one after transplantation, 4 our patient received nivolumab 19 months after alloSCT. Thus, GVHD might be more responsive to PD1/PD-L1 inhibition during the early phase of transplantation potentially triggering severe GVH reactions in the context of conditioning-related inflammation of host tissues.…”

“…In fact, increased GVHD-related lethality has been demonstrated in a murine model of acute GVHD when blocking PD-L1. 4 Recently, a report on a patient receiving pembrolizumab for malignant melanoma about 20 years after alloSCT reported no development of GVHD. 5 However, there were no data on donor chimerism reported and lack of donor immune cells might be a reasonable cause for lack of GVHD development.…”

Fatal GvHD induced by PD-1 inhibitor pembrolizumab in a patient with Hodgkin’s lymphoma

“…16 PD-L2 is expressed on dendritic cells, macrophages and bone marrow-derived mast cells. Saha et al 17 demonstrated the critical importance of PD-1/PD-L1, but not PD-1/ PD-L2 pathway in the regulation of GvHD. In a murine model, they demonstrated the enhanced expression of PD-L1 ligand in target tissues during acute GvHD.…”

“…This increase in T-cell activity was preferentially noted in GvHD target organs like colon and ileum where a loss of epithelial cell integrity was observed. 17 In addition to PD-1, PD-L1 also binds to CD80 on the surface of T cells. Using an alloimmune model of GvHD, Deng et al 18 showed that outcome of PD-L1/CD80 interaction is influenced by the presence or absence of PD-1.…”