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

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.

• Authors: 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, Andrew Futreal
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 6071 (10 18 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34663807 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Immune Checkpoint Inhibitors
• Programmed Cell Death 1 Receptor
• Receptors, Antigen, T-Cell
• Nivolumab
• Granzymes
• Azacitidine

Topics

• Aged
• Aged, 80 and over
• Azacitidine (therapeutic use)
• Bone Marrow (drug effects, immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology, metabolism)
• Chromosome Deletion
• Chromosomes, Human, Pair 7 (genetics)
• Drug Resistance, Neoplasm (genetics)
• Granzymes (metabolism)
• Humans
• Immune Checkpoint Inhibitors (therapeutic use)
• Leukemia, Myeloid, Acute (drug therapy, genetics, immunology)
• Middle Aged
• Nivolumab (therapeutic use)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Receptors, Antigen, T-Cell (genetics, metabolism)
• Single-Cell Analysis
• T-Lymphocyte Subsets (drug effects, immunology, metabolism)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Transcriptome (drug effects)