Pretransplant nivolumab further enhanced Treg expansion after posttransplant cyclophosphamide; another aspect for immune tolerance by PTCy after nivolumab

Abstract

We read the article by Nieto et al. with interest [1]. The authors demonstrated that pretransplant nivolumab resulted in a high frequency of IFN-γ-producing effector T cells that might contribute severe graft-versus-host disease (GVHD) after transplant. They also showed that posttransplant cyclophosphamide (PTCy) abrogated the immune activations and could suppress GVHD to the mild levels. The data were comprehensive and convincing, but the analyses of regulatory T cells (Tregs) were limited to just a one-time point. In general, PTCy can contribute to enhancing Treg recovery as well as suppressing alloreactive effector T cells [2–4]. Our previous study suggested that programmed cell death 1 (PD-1) plays an important role in Treg homeostasis [5]. Moreover, by using a murine HSCT model, we recently demonstrated that pretransplant PD-1 blockade critically impaired posttransplant Treg recovery, leading to severe GVHD, and PTCy could restore Treg homeostasis and ameliorate GVHD [6]. Based on these findings, we herein analyzed the chronological recovery of Treg after PTCy in patients with or without pretransplant nivolumab therapy and considered the impact of nivolumab on Treg homeostasis after PTCy-based transplant. We experienced three cases of chemotherapy-refractory classical Hodgkin lymphoma, those were treated by nivolumab as a salvage therapy and followingly received HLAhaploidentical HSCT. The clinical courses of the three patients are described in Supplementary Fig. 1. We compared the detailed immune reconstitutions of patients receiving pretransplant nivolumab followed by PTCy-based HLAhaploidentical HSCT (“Nivo→PTCy”; Cases 1 and 2) and ATG-based HLA-haploidentical HSCT (“Nivo→ATG”; Case 3) with those of patients who received PTCy-based HLA-haploidentical HSCT without ICI (“control-PTCy”; Cases 4–6) and ATG-based HLA-haploidentical HSCT without ICI (“control-ATG”; Cases 7–9), as respective controls. Clinical data and frozen samples were collected from these nine patients. Detailed patient characteristics and transplant outcomes are summarized in supplementary Table 1. All patients provided written informed consent before sample collection. To understand the homeostasis of each T cell subset post-transplant, we first examined PD-1 expression and cell proliferation of T cells after transplant (Supplementary Fig. 2). PD-1 expression levels in patients without pretransplant nivolumab were elevated within 2 weeks after transplantation, especially in the control-ATG group (Supplementary Fig. 2A). By contrast, the PD-1 expression level in patients who received pretransplant nivolumab was even lower than that of healthy controls. Cell proliferation was assessed based on Ki67-expression in each T cell subset (Supplemental Fig. 2B). In cases without pretransplant nivolumab, cell proliferation was more active in each T cell subset for patients in the control-ATG group than for patients in the control-PTCy group (Supplementary Fig. 2B). Pretransplant nivolumab markedly increased the * Ken-ichi Matsuoka [email protected]