The PD-1 Axis Enforces an Anatomical Segregation of CTL Activity that Creates Tumor Niches after Allogeneic Hematopoietic Stem Cell Transplantation

Michonneau, David; Sagoo, Pervinder; Breart, Béatrice; Garcia, Zacarias; Celli, Susanna; Bousso, Philippe

doi:10.1016/j.immuni.2015.12.008

Cited by 76 publications

(74 citation statements)

References 50 publications

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“…[9][10][11] Our results strongly support the hypothesis that prior checkpoint blockade affects HSCT outcomes, based on several aspects of this cohort. In terms of toxicity, we observed a higher than expected rate of early severe transplant-related complications.…”

Section: Discussionsupporting

confidence: 85%

“…8 Specifically, residual PD-1 inhibition peri-and post-HSCT could enhance allogeneic T-cell responses, which could augment the graft-versus-tumor (GVT) effect but also increase the incidence or severity of immune complications. Animal models demonstrate that PD-1 blockade early after allogeneic HSCT may augment GVT in anatomic niches that are susceptible to relapse, 9 but could also result in higher rates of acute graft-versus-host disease (GVHD) and increased GVHD lethality. 10,11 Early clinical trials suggest that checkpoint blockade therapy with nivolumab or ipilimumab (IPI) as treatment of relapse after HSCT could be effective with a tolerable side-effect profile.…”

Section: Introductionmentioning

confidence: 99%

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Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma

Merryman

Kim

Zinzani

et al. 2017

Blood

208

184

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Key Points• HSCT after PD-1 blockade is feasible, although may be associated with increased early immune toxicity.• PD-1 blockade may cause persistent depletion of PD1 1T cells and alterations in T-cell differentiation impacting subsequent treatment.Anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are being increasingly tested in patients with advanced lymphoma. Following treatment, many of those patients are likely to be candidates for allogeneic hematopoietic stem cell transplant (HSCT). However, the safety and efficacy of HSCT may be affected by prior PD-1 blockade. We conducted an international retrospective analysis of 39 patients with lymphoma who received prior treatment with a PD-1 inhibitor, at a median time of 62 days (7-260) before HSCT. After a median follow-up of 12 months, the 1-year cumulative incidences of grade 2-4 and grade 3-4 acute graft-versus-host disease (GVHD) were 44% and 23%, respectively, whereas the 1-year incidence of chronic GVHD was 41%. There were 4 treatment-related deaths (1 from hepatic sinusoidal obstruction syndrome, 3 from early acute GVHD). In addition, 7 patients developed a noninfectious febrile syndrome shortly after transplant requiring prolonged courses of steroids. One-year overall and progression-free survival rates were 89% (95% confidence interval [CI], 74-96) and 76% (95% CI, 56-87), respectively. One-year cumulative incidences of relapse and nonrelapse mortality were 14% (95% CI, 4-29) and 11% (95% CI, 3-23), respectively. Circulating lymphocyte subsets were analyzed in 17 patients. Compared with controls, patients previously treated with PD-1 blockade had significantly decreased PD-1 1 T cells and decreased ratios of T-regulatory cells to conventional CD4 and CD8 T cells. In conclusion, HSCT after PD-1 blockade appears feasible with a low rate of relapse. However, there may be an increased risk of early immune toxicity, which could reflect long-lasting immune alterations triggered by prior PD-1 blockade. (Blood. 2017;129(10):1380-1388

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma

Merryman

Kim

Zinzani

et al. 2017

Blood

208

184

View full text Add to dashboard Cite

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“…The pattern for CD8 + T cells in the liver fell in between, as indicated by the ratio of PD-1 to CD80 ( Figure 8A). Consistent with a previous report (44), non-T cells such as CD11c + DCs and CD11b/ Gr-1 + myeloid cells in the spleen expressed much higher levels of PD-L1 as compared with those in the liver and colon. Anti-CD4 treatment did not significantly change the high expression of PD-L1 by non-T cells in the spleen (Supplemental Figure 20).…”

Section: Figure 4 Depletion Of Donor Cd4 + T Cells Increases Serum Isupporting

confidence: 92%

PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells

Ni¹,

Song²,

Cassady³

et al. 2017

Journal of Clinical Investigation

103

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Programmed death ligand-1 (PD-L1) interacts with programmed death-1 (PD-1) and the immunostimulatory molecule CD80 and functions as a checkpoint to regulate immune responses. The interaction of PD-L1 with CD80 alone has been shown to exacerbate the severity of graft-versus-host disease (GVHD), whereas costimulation of CD80 and PD-1 ameliorates GVHD. Here we have demonstrated that temporary depletion of donor CD4+ T cells early after hematopoietic cell transplantation effectively prevents GVHD while preserving strong graft-versus-leukemia (GVL) effects in allogeneic and xenogeneic murine GVHD models. Depletion of donor CD4+ T cells increased serum IFN-γ but reduced IL-2 concentrations, leading to upregulation of PD-L1 expression by recipient tissues and donor CD8+ T cells. In GVHD target tissues, the interactions of PD-L1 with PD-1 on donor CD8+ T cells cause anergy, exhaustion, and apoptosis, thereby preventing GVHD. In lymphoid tissues, the interactions of PD-L1 with CD80 augment CD8+ T cell expansion without increasing anergy, exhaustion, or apoptosis, resulting in strong GVL effects. These results indicate that the outcome of PD-L1-mediated signaling in CD8+ T cells depends on the presence or absence of CD4+ T cells, the nature of the interacting receptor expressed by CD8+ T cells, and the tissue environment in which the signaling occurs.

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“…However, the clinical application of the HCT is limited by leukemia relapse [3] and life-threatening complications, such as graft-versus-host disease (GVHD) [4, 5], infection [6–8], conditioning regimen-related toxicities [9–11], and transplant-associated thrombotic microangiopathy (TMA) [12–14] as well, which are more common in patients receiving HLA locus mismatched grafts. In clinical practice, it is increasingly difficult to identify a HLA locus completely matched donor in the presence of highly polymorphic HLA alleles.…”

Section: Introductionmentioning

confidence: 99%

Clinical implications of HLA locus mismatching in unrelated donor hematopoietic cell transplantation: a meta-analysis

et al. 2017

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It remains controversial that the impacts of individual HLA locus mismatches on clinical outcomes of patients receiving unrelated-donor hematopoietic cell transplantation (HCT), as compared to HLA allele matched controls. We conducted a meta-analysis to address these issues. Four databases (PubMed, Embase, Web of Science and the Cochrane Library) were searched to select eligible studies. All donor-recipient pairs were high-resolution typing for HLA-A, -B, -C, -DRB1, DQB1 and DPB1 loci. Multivariate-adjusted hazard ratios (HRs) were extracted and pooled using a random-effects model. A total of 36 studies were included, with 100,072 patients receiving HCT. Surprisingly, we found that HLA-DQB1 locus mismatches had no significantly increased risk of multiple outcomes including acute and chronic graft-versus-host disease (GVHD), overall mortality and disease relapse (HR, 1.07; P = .153; HR, 1.07; P = .271; HR, 1.09; P = .230; HR, 1.07; P = .142 and HR, 1.02; P = .806, respectively). Mismatched HLA-DPB1 was significantly associated with a reduced risk of disease relapse (HR, 0.74; P < .001) but not with increased risks of transplant-related mortality (TRM) and overall mortality (HR, 1.09; P = .591; I2 = 74.2% and HR, 1.03; P = .460, respectively). In conclusion, HLA-DQB1 locus mismatches is a permissive mismatching. HLA-DPB1 locus mismatches significantly protect against leukemia relapse. Refining effects of individual HLA locus mismatches contributes to predicting prognosis of patients receiving unrelated donor HCT.

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The PD-1 Axis Enforces an Anatomical Segregation of CTL Activity that Creates Tumor Niches after Allogeneic Hematopoietic Stem Cell Transplantation

Cited by 76 publications

References 50 publications

Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma

Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma

PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells

Clinical implications of HLA locus mismatching in unrelated donor hematopoietic cell transplantation: a meta-analysis

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