Mapping the evolution of T cell states during response and resistance to adoptive cellular therapy Journal Article
| Authors: | Bachireddy, P.; Azizi, E.; Burdziak, C.; Nguyen, V. N.; Ennis, C. S.; Maurer, K.; Park, C. Y.; Choo, Z. N.; Li, S.; Gohil, S. H.; Ruthen, N. G.; Ge, Z.; Keskin, D. B.; Cieri, N.; Livak, K. J.; Kim, H. T.; Neuberg, D. S.; Soiffer, R. J.; Ritz, J.; Alyea, E. P.; Pe'er, D.; Wu, C. J. |
| Article Title: | Mapping the evolution of T cell states during response and resistance to adoptive cellular therapy |
| Abstract: | To elucidate mechanisms by which T cells eliminate leukemia, we study donor lymphocyte infusion (DLI), an established immunotherapy for relapsed leukemia. We model T cell dynamics by integrating longitudinal, multimodal data from 94,517 bone marrow-derived single T cell transcriptomes in addition to chromatin accessibility and single T cell receptor sequencing from patients undergoing DLI. We find that responsive tumors are defined by enrichment of late-differentiated T cells before DLI and rapid, durable expansion of early differentiated T cells after treatment, highly similar to “terminal” and “precursor” exhausted subsets, respectively. Resistance, in contrast, is defined by heterogeneous T cell dysfunction. Surprisingly, early differentiated T cells in responders mainly originate from pre-existing and novel clonotypes recruited to the leukemic microenvironment, rather than the infusion. Our work provides a paradigm for analyzing longitudinal single-cell profiling of scenarios beyond adoptive cell therapy and introduces Symphony, a Bayesian approach to infer regulatory circuitry underlying T cell subsets, with broad relevance to exhaustion antagonists across cancers. © 2021 The Author(s) |
| Keywords: | leukemia; immunotherapy; donor lymphocyte infusion; gene regulatory networks; exhaustion; allogeneic hematopoietic stem cell transplant; atac-seq; scrna-seq; probabilistic models; statistical machine learning |
| Journal Title: | Cell Reports |
| Volume: | 37 |
| Issue: | 6 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2021-11-09 |
| Start Page: | 109992 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2021.109992 |
| PROVIDER: | scopus |
| PUBMED: | 34758319 |
| PMCID: | PMC9035342 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2021 -- Source: Scopus |
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