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 S. Im, Patrick K. Reville, Zoe Alaniz, Wei Wang, Ruiping Wang, Feng Wang, Gheath Alatrash, 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 R. Parra, Wei Lü, Auriole Tamegnon, Guillermo Garcia‐Manero, Michael R. Green, Padmanee Sharma, James P. Allison, Steven M. Kornblau, Kunal Rai, Linghua Wang, Naval Daver, P. Andrew Futreal
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.