Using bone marrow (BM) biopsies of a longitudinal cohort of relapsed CML patients treated with CD8-depleted donor lymphocyte infusion (DLI), Bachireddy and Azizi et al. defined intratumoral T cell dynamics in relationship to clinical response. Integrating single T cell transcriptomes, bulk chromatin accessibility profiles, and single TCR sequencing defined responders with the enrichment of terminally exhausted (late differentiated) T cell subsets before DLI, and expansion of precursor exhausted (early differentiated) T cells after treatment (originating from pre-existing and novel clonotypes). Non-responders demonstrated multiple types of T cell dysfunction.
Contributed by Shishir Pant
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.
Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Bosto
Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Hematopoietic Biology & Malignancy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research, Austin, TX 78701, USA. Electronic address: pbachireddy@mdanderson.org. (2) Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Biomedical Engineering and Irving Institute for Cancer Dynamics, Columbia University, New York, NY 10027, USA. Electronic address: ea2690@columbia.edu. (3) Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY 10065, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA. (7) Department of Biomedical Engineering and Irving Institute for Cancer Dynamics, Columbia University, New York, NY 10027, USA. (8) Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (9) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (10) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (12) Department of Hematopoietic Biology & Malignancy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (13) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (14) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (16) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (17) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (18) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA. (20) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA. (21) Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute of Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: peerd@mskcc.org. (22) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: cwu@partners.org.
