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

Hussein A. Abbas, Dapeng Hao, Katarzyna Tomczak, Praveen Barrodia, Jin Seon Im, Patrick K. Reville, Zoe Alaniz, Wei Wang, Ruiping Wang, Feng Wang, Gheath Al-Atrash, Koichi Takahashi, Jing Ning, Maomao Ding, Hannah C. Beird, Jairo T. Mathews, Latasha Little, Jianhua Zhang, Sreyashi Basu, Marina Konopleva, Mario L. Marques-Piubelli, Luisa M. Solis, Edwin Roger Parra, Wei Lu, Auriole Tamegnon, Guillermo Garcia-Manero, Michael R. Green, Padmanee Sharma, James P. Allison, Steven M. Kornblau, Kunal Rai (), Linghua Wang (), Naval Daver () and Andrew Futreal ()
Additional contact information
Hussein A. Abbas: University of Texas M D Anderson Cancer Center
Dapeng Hao: University of Texas M D Anderson Cancer Center
Katarzyna Tomczak: University of Texas M D Anderson Cancer Center
Praveen Barrodia: University of Texas M D Anderson Cancer Center
Jin Seon Im: University of Texas MD Anderson Cancer Center
Patrick K. Reville: University of Texas M D Anderson Cancer Center
Zoe Alaniz: University of Texas MD Anderson Cancer Center
Wei Wang: University of Texas MD Anderson Cancer Center
Ruiping Wang: University of Texas M D Anderson Cancer Center
Feng Wang: University of Texas M D Anderson Cancer Center
Gheath Al-Atrash: University of Texas MD Anderson Cancer Center
Koichi Takahashi: University of Texas MD Anderson Cancer Center
Jing Ning: University of Texas MD Anderson Cancer Center
Maomao Ding: University of Texas MD Anderson Cancer Center
Hannah C. Beird: University of Texas M D Anderson Cancer Center
Jairo T. Mathews: University of Texas MD Anderson Cancer Center
Latasha Little: University of Texas M D Anderson Cancer Center
Jianhua Zhang: University of Texas M D Anderson Cancer Center
Sreyashi Basu: University of Texas MD Anderson Cancer Center
Marina Konopleva: University of Texas MD Anderson Cancer Center
Mario L. Marques-Piubelli: University of Texas MD Anderson Cancer Center
Luisa M. Solis: University of Texas MD Anderson Cancer Center
Edwin Roger Parra: University of Texas MD Anderson Cancer Center
Wei Lu: University of Texas MD Anderson Cancer Center
Auriole Tamegnon: University of Texas MD Anderson Cancer Center
Guillermo Garcia-Manero: University of Texas MD Anderson Cancer Center
Michael R. Green: University of Texas M D Anderson Cancer Center
Padmanee Sharma: University of Texas MD Anderson Cancer Center
James P. Allison: University of Texas MD Anderson Cancer Center
Steven M. Kornblau: University of Texas MD Anderson Cancer Center
Kunal Rai: University of Texas M D Anderson Cancer Center
Linghua Wang: University of Texas M D Anderson Cancer Center
Naval Daver: University of Texas MD Anderson Cancer Center
Andrew Futreal: University of Texas M D Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26282-z

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