Early Immune Reconstitution and Relapse-Related Characteristics in Acute Myeloid Leukemia Patients after Transplantation
Authors: Dai Weiqian , Hao Sha , Wu Linjie , Zhao Xueying , Dong Fang , Wang Lisha , Jiang Erlie , Cheng Tao 
Published: December 2024

Hematopoietic stem cell transplantation stands as a leading therapeutic approach for a spectrum of hematologic disorders, including benign and malignant diseases. Among these methods, haploidentical hematopoietic stem cell transplantation (haplo-PBSCT) has emerged as a predominant strategy. The risk of post-transplant relapse poses a significant challenge to patient outcomes and quality of life. Post-transplant immune reconstitution is pivotal for prognosis, with early immune recovery being particularly critical for the long-term survival of patients afflicted with malignant hematologic diseases. Building on our previous research into post-transplant hematopoietic reconstitution patterns (Huo, et al., Sci Immunol. 2023), this study delves into the nuances of early immune reconstitution following haplo-PBSCT in acute myeloid leukemia (AML) patients and the immunological signatures associated with early relapse.

We compared the early immune reconstitution in AML (a malignant hematologic condition), and aplastic anemia (AA, a myeloproliferative disorder) to spotlight the role of immune cells in the initial phases of recovery (within 60 days post-transplantation) in order to dissect the anti-leukemia effects of immune cells. Notably, we observed a marked disparity in monocyte and T cell profiles post-transplantation. Specifically, AML patients exhibited a pronounced increase in monocyte counts 30 days post-transplant, with intermediate monocytes showing the starkest contrast. These intermediate monocytes in AML were implicated in pathways linked to cell proliferation, differentiation, protein synthesis, and tumorigenesis. Furthermore, at 60 days post-transplantation, T cells demonstrated significant variance, with CD8 effector/memory T cells actively participating in immune activation and signaling pathways pertinent to anti-tumor and tumorigenesis processes in AML. Intriguingly, the communication between monocytes and T cells in AML patients was considerably stronger at the 30-day, implicating signaling pathways such as TGFb/Galectin/ADGRE5, all of which are intricately tied to tumor progression.

To further elucidate the dynamics of immune cell behavior preceding and following relapse, we selected a cohort of three AML patients with continuous complete remission (CCR) and three with early relapse (ER), collecting bone marrow at 1 month, 3 months (prior to relapse), and at the time of relapse for single-cell transcriptome and TCR profiling. The starkest differences between CCR and ER patients were observed in the intermediate and non-classical monocytes at 30 days, and CD8 effector T cells at 90 days post-transplantation. The cellular crosstalk between monocytes and T cells in ER patients was significantly heightened at both time points, with signaling pathways such as MIF, SELPLE, ALCAM, and others associated with cancer promotion, being notably upregulated.

In the prelude to relapse, AML patients displayed heightened proliferation and differentiation of CD4 naïve T cells, alongside augmented signaling in CD8 naïve T cells. Concurrently, the signal intensity of CD38 high T cells escalated at the time of relapse, suggesting a potential role for T cells in exerting anti-leukemic effects or succumbing to exhaustion. Both CCR and ER patients exhibited distinct TCR clonal preferences, with certain TCR clones potentially exhibiting high affinity for AML-associated peptides, capable of precise and rapid leukemia cell recognition and killing.

This study not only contrasts the early immune reconstitution patterns across different hematologic diseases and different outcomes within the same disease post haplo-PBSCT but also sheds light on the graft-versus-leukemia (GVL) effect of T cells and TCR clonal preferences post-transplantation. Our findings offer valuable insights for clinical management and the prevention of post-transplant relapse, with the aspiration to develop TCR-based products designed for the precise and efficient elimination of leukemia cells.