Azacitidine-induced reconstitution of the bone marrow T cell repertoire is associated with superior survival in AML patients

Juliane Grimm,Mascha Binder,Haifa Kathrin Al-Ali,Nadja Jäkel,Christine Dierks,Lisa Paschold,Edith Willscher,Donjete Simnica,Susann Schulze

doi:10.1038/s41408-022-00615-7

Abstract

Hypomethylating agents (HMA) like azacitidine are licensed for the treatment of acute myeloid leukemia (AML) patients ineligible for allogeneic hematopoietic stem cell transplantation. Biomarker-driven identification of HMA-responsive patients may facilitate the choice of treatment, especially in the challenging subgroup above 60 years of age. Since HMA possesses immunomodulatory functions that constitute part of their anti-tumor effect, we set out to analyze the bone marrow (BM) immune environment by next-generation sequencing of T cell receptor beta (TRB) repertoires in 51 AML patients treated within the RAS-AZIC trial. Patients with elevated pretreatment T cell diversity (11 out of 41 patients) and those with a boost of TRB richness on day 15 after azacitidine treatment (12 out of 46 patients) had longer event-free and overall survival. Both pretreatment and dynamic BM T cell metrics proved to be better predictors of outcome than other established risk factors. The favorable broadening of the BM T cell space appeared to be driven by antigen since these patients showed significant skewing of TRBV gene usage. Our data suggest that one course of AZA can cause reconstitution to a more physiological T cell BM niche and that the T cell space plays an underestimated prognostic role in AML.Trial registration: DRKS identifier: DRKS00004519

Highlights

Acute myeloid leukemia (AML) remains a fatal disease with only around 10–15% long-term survival in patients older than 60 years [1, 2]
AML is characterized by an immunosuppressive microenvironment with multiple mechanisms being involved in immune escape of AML blasts: Part of it is thought to be mediated by soluble factors such as cytokines since some signatures have been shown to be associated with overall survival in AML patients [5–8]
Deep sequencing of T cell receptor beta (TRB) repertoires in AML patients treated with AZA To gain insights into the T cell bone marrow (BM) niche of AML patients and its potential transformation through treatment with an Hypomethylating agents (HMA), we performed immuno-NGS on BM T cells of 51 AML patients as well as 13 healthy donors (HD)

Summary

Introduction

Acute myeloid leukemia (AML) remains a fatal disease with only around 10–15% long-term survival in patients older than 60 years [1, 2]. AML is characterized by an immunosuppressive microenvironment with multiple mechanisms being involved in immune escape of AML blasts: Part of it is thought to be mediated by soluble factors such as cytokines since some signatures have been shown to be associated with overall survival in AML patients [5–8]. Other mechanisms of impaired immunosurveillance in AML rely on circumventing target recognition and subsequent cytotoxic T cell responses, e.g. by loss of HLA class II expression on the AML blasts after allogeneic HSCT [9]. AML patients—and especially patients with refractory disease or relapse after HSCT—display higher frequencies of exhausted T cells compared to healthy donors [12–19]. The malfunctioning T cell space in AML is characterized by a general down-regulation of genes involved in T cell activation [20], as well as a skewed T cell repertoire with reduced diversity compared to healthy donors [19, 21, 22]

Methods

Results

Conclusion