Mapping the evolution of T cell states during response and resistance to adoptive cellular therapy

Cell Rep. 2021 Nov 9;37(6):109992. doi: 10.1016/j.celrep.2021.109992.


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.

Keywords: ATAC-seq; allogeneic hematopoietic stem cell transplant; donor lymphocyte infusion; exhaustion; gene regulatory networks; immunotherapy; leukemia; probabilistic models; scRNA-seq; statistical machine learning.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Clonal Evolution
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Leukemia / immunology*
  • Leukemia / pathology
  • Leukemia / therapy
  • Longitudinal Studies
  • Lymphocyte Activation / immunology*
  • Lymphocyte Transfusion / methods*
  • Neoplasm Recurrence, Local / immunology*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Recurrence, Local / therapy
  • Stem Cell Transplantation / methods*
  • T-Lymphocytes / immunology*
  • Tissue Donors
  • Transplantation, Homologous