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

Abstract

A B S T R A C T Blockade of the T-cell exhaustion marker PD-1 to re-energize the immune response is emerging as a promising cancer treatment. Relapse of hematologic malignancy after allogeneic stem cell transplantation limits the success of this approach, and PD-1 blockade may hold therapeutic promise. However, PD-1 expression and its relationship with post-transplant relapse is poorly described. Because the donor immunity is activated by alloresponses, PD-1 expression may differ from nontransplanted individuals, and PD-1 blockade could risk graft-versus-host disease.Here we analyzed T-cell exhaustion marker kinetics and their relationship with leukemia relapse in 85 patients undergoing myeloablative T-cell-depleted HLA-matched stem cell transplantation. At a median follow-up of 3.5 years, 35 (44%) patients relapsed. PD-1 expression in CD4 and CD8 T cells was comparably elevated in relapsed and nonrelapsed cohorts. Helios + regulatory T cells and CD8 effector memory cells at day 30 emerged as independent predictors of relapse. Although leukemia antigen-specific T cells did not overexpress PD-1, single-cell analysis revealed LAG3 and TIM3 overexpression at relapse. These findings indicate that PD-1 is an unreliable marker for leukemia-specific T-cell exhaustion in relapsing patients but implies other exhaustion markers and suppressor cells as relapse biomarkers.Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation.

Progress and Clinical Application of Single-Cell Transcriptional Sequencing Technology in Cancer Research

“…ScTrio-Seq has further developed single-cell multi-omics technologies by combining three omics methods, genomics, transcriptomics, and epigenomics. The spatial information of individual cells in a tissue is usually lost during the isolation step, so individual cell sequencing data usually do not show how cells organize to achieve coordinated functions within the target tissue ( 26 ). The field of single-cell spatial transcription is under intensive investigation, and many new technologies have been developed to maintain or restore spatial information of sequenced single cells, such as seqFISH (sequential fluorescence in situ hybridization of RNA) ( 86 ), MERFISH (Multiplexed error-robust fluorescence in situ hybridization) ( 87 ), FISSEQ (fluorescent in situ sequencing) ( 88 ), or TIVA (Transcriptome in vivo analysis) ( 89 ).…”

“…The kinetics of T cell exhaustion and its relationship with leukemia recurrence were analyzed by scRNA-seq in patients undergoing allo-SCT. Although leukemia antigen-specific T cells do not overexpress PD-1, LAG3 and TIM3 are over expressed during relapse ( 26 ). So we could target LAG3 and TIM3 as a new therapy approach.…”

Immune Reconstitution After Allogeneic Haematopoietic Cell Transplantation: From Observational Studies to Targeted Interventions

“…Noteworthy, T regs may also play a role in the graft-vs.leukaemia reaction. In a series of 85 patients with leukemic relapses after HCT, a higher content of Helios + T reg at day +30 within the CD4 compartment was accompanied by a higher incidence and earlier occurrence of leukemic relapse (127). In contrast, checkpoint blockade which is applied to increase antitumor immunity both in the autologous and the allogeneic setting is known to inhibit T regs .…”

“…Further and more homogenous studies are required to better characterise patients in whom the potential benefit of immune checkpoint blockade overrides its risks. Noteworthy, in a study of 85 patients after allo HCT for various haematologic malignancies, LAG-3 and TIM-3 rather than PD-1 were overexpressed on T-cells of relapsing patients, indicating that other exhaustion markers beyond the PD-1-PD-L1 axis might be interesting and druggable targets to enhance GvL after allo HCT ( 127 ).…”

The Role of Immune Checkpoints after Cellular Therapy

“…Several studies have been published analyzing the expression of inhibitory checkpoints in the context of disease relapse after allo-HCT. During the early post-transplantation phase, PD-1 was shown to be ubiquitously overexpressed on T cells, but interestingly without being a reliable predictive marker of potential disease relapse [43]. Hutten and colleagues found that high co-expression of PD-1, TIGIT, and killer cell lectin-like receptor subfamily member 1 (KLRG-1) on minor histocompatibility antigen (MiHA)-reactive CD8 + T cells correlates with disease relapse after allo-HCT [44].…”