Single cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy

Hussein A Abbas,Andrew Futreal,Naval Daver,Michael R Green,Hannah C Beird,Linghua Wang,Jairo T Mathews,Marina Konopleva,Wei Wang,Latasha Little,Zoe Alaniz,Auriole Tamegnon,Praveen Barrodia,Padmanee Sharma,Patrick K Reville,Jianhua Zhang,Ruiping Wang,Feng Wang,Kunal Rai,James P Allison,Dapeng Hao,Koichi Takahashi,Edwin R Parra ,Jin S Im ,Wei Lü ,Gheath Alatrash ,Guillermo Garcia‐Manero ,Mario L Marques‐Piubelli ,Maomao Ding,Sreyashi Basu,Jing Ning,Luisa M Solis,Steven M Kornblau,Katarzyna Tomczak

doi:10.1038/s41467-021-26282-z

Abstract

In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires. Here, we show by paired single-cell RNA analysis and TCR repertoire profiling of bone marrow cells in relapsed/refractory acute myeloid leukemia patients pre/post azacytidine+nivolumab treatment that the disease-related T cell subsets are highly heterogeneous, and their abundance changes following PD-1 blockade-based treatment. TCR repertoires expand and primarily emerge from CD8+ cells in patients responding to treatment or having a stable disease, while TCR repertoires contract in therapy-resistant patients. Trajectory analysis reveals a continuum of CD8+ T cell phenotypes, characterized by differential expression of granzyme B and a bone marrow-residing memory CD8+ T cell subset, in which a population with stem-like properties expressing granzyme K is enriched in responders. Chromosome 7/7q loss, on the other hand, is a cancer-intrinsic genomic marker of PD-1 blockade resistance in AML. In summary, our study reveals that adaptive T cell plasticity and genomic alterations determine responses to PD-1 blockade in acute myeloid leukemia.

Highlights

1234567890():,; In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires
We conducted paired Single cell RNA (scRNA) and scTCR profiling on 22 (8 pre- and 14 post-treatment) bone marrow (BM) aspirates from 8 R/R AML treated with ICB-based therapy on NCT02397720 (Fig. 1A)
We leveraged paired scRNA and scTCR profiling of AML BMs before and after treatment to understand the dynamics of T cells and their repertoires

Summary

Introduction

1234567890():,; In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires. TCR repertoire profiling is used to examine the intratumoral T cell responses and as a biomarker of response to immune checkpoint therapy[19,20,21,22,23,24,25,26,27,28], and revealed the expansion of novel clones in skin cancers following PD-1 blockade[28] While generalizing these observations is tempered by small patient numbers, the depth of the analysis allows for high resolution dissection of T cells and their repertoires. Our work reveals that deletion in chromosome 7/7q is an intrinsic AML biomarker of resistance to ICB-therapy Findings from this analysis afford a deep characterization of AML T-cell landscape and can be extrapolated to interpret the T cell dynamics in response to PD-1 blockade-therapy in other hematologic malignancies by identifying BM residing T cell subsets and tumor intrinsic factors that could be leveraged therapeutically

Methods

Results

Conclusion