Reversal of T Cell Exhaustion by the First Donor Lymphocyte Infusion Is Associated with the Persistently Effective Antileukemic Responses in Patients with Relapsed AML after Allo-HSCT

Abstract

Donor lymphocyte infusion (DLI) is an effective approach to treat acute myelogenous leukemia (AML) relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) that significantly improves the survival of relapsed patients. However, the mechanism of an effective antileukemic response following DLI in AML relapse remains elusive. Here, we investigated the role of T cell exhaustion in AML relapse after allo-HSCT in prospective cohorts of 41 patients with the first AML relapse and 41 nonrelapsed AML control subjects after allo-HSCT and determined whether DLI exerts effective antileukemic effects by reversing T cell exhaustion in the relapsed cohorts by detecting the phenotypes and functions of T cells using flow cytometry. We found that both CD4 and CD8 T cells experienced exhaustion with upregulated coexpression of PD-1 and Tim-3, and functional impairments in cytokine production, proliferation, and cytotoxic potentials. The reversal of T cell exhaustion by the first DLI is associated with persistent complete remission in relapsed AML patients. In addition, the reversal of T cell-exhausted status after successful DLI in bone marrow was concurrent with the mitigated inversion of CD4/CD8 T cell ratio. In conclusion, our study shows a clinical correlation between T cell exhaustion and AML relapse after allo-HSCT, and uncovers the role of reversing T cell exhaustion in the antileukemic response by DLI and identifies possible immunological markers to evaluate and predict the graft-versus-leukemia effects induced by DLI.

Can the New and Old Drugs Exert an Immunomodulatory Effect in Acute Myeloid Leukemia?

“…Coherently, it has been shown that sorafenib may indirectly regulate the activation of CD8+ T-lymphocytes and natural killer cells (NKs) by restoring the production of interleukin-15 (IL-15) in FLT3-ITD-mutated clones (Figure 1) [14]. In the leukemic clone, sorafenib activity may also be extended to an increase of IFN-γ production, which may reverse the downregulation of MHC Class II, known to be involved in post-allo-HSCT relapse [18]. The data regarding sorafenib activity on T-regs are conflicting.…”

Harnessing the immune system after allogeneic stem cell transplant in acute myeloid leukemia

“…Post‐transplant AML relapse is driven in part by loss of leukemic‐specific T cells and loss of T cell function. DLI has been found to increase anti‐leukemic T cells, but also reverses T cell exhaustion through increased IFN‐γ production and reduced T cell inhibitory receptors, such as programmed cell death protein 1 (PD‐1) and T cell immunoglobulin and mucin domain 3 (Tim‐3) . As with allo‐SCT, the major obstacle with DLI is to maximize the GVL effect while minimizing GVHD.…”

“…Sorafenib has been found to increase IL‐15 production in mutant FLT3‐ITD + leukemia cells, which enhances the GVL effect by augmenting CD8 + CD107a + IFN‐γ − + T cells with features of longevity—that is, high levels of Bcl‐2 and low levels of PD‐1. Sorafenib also increases IFN‐γ production, particularly in responders, which may reverse the downregulation of MHC Class II that has been implicated in AML relapse following non‐haploidentical transplant . In a study involving 53 patients with FLT3‐ITD AML (51 with relapsed or refractory disease with 29 having undergone prior allo‐SCT) who were treated with sorafenib monotherapy, 15 patients (23%) achieved complete remission, including seven patients (24%) with prior allo‐SCT.…”

Targeting Immune Signaling Checkpoints in Acute Myeloid Leukemia

“…To minimalize the side effects mediated by the recognition of fragment crystallizable (Fc) region, atezolizumab and durvalumab have a point mutation in the Fc domain; thus, they did not induce the cytotoxicity of the antibody-dependent cellular cytotoxicity, nor the complement-dependent cytotoxicity. The upregulation of checkpoint molecules was observed after alloHSCT and therapy with hypomethylating agents, pointing to a potential clinical application in these settings [53,54]. Moreover, a higher PD-1 expression on T cells was strongly associated with leukemia relapse, post-alloHSCT [55].…”