To uncover the determinants of anti-PD-1 response in Richter syndrome (RS), Parry et al. performed scRNAseq in serial marrow samples from nivolumab-treated RS patients and identified a ZNF683high CD8+ T cell population (Cluster 1; Cl1) enriched in responders. The TF ZNF683 directly targets key T cell genes (TCF7, LMO2, CD69) and regulates pathways of T cell activation and cytotoxicity, marking an intermediate exhausted population evolving from stem-like memory cells and divergent from terminally exhausted CD8+ T cells. The Cl1 signature and ZNF683high expression in peripheral blood of RS and solid tumor patients was positively associated with ICB response.
Contributed by Shishir Pant
ABSTRACT: Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyze single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 patients with RS. Response is associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells. This signature overlaps with that of tumor-infiltrating populations from anti-PD-1 responsive solid tumors. ZNF683 is found to directly target key T cell genes (TCF7, LMO2, CD69) and impact pathways of T cell cytotoxicity and activation. Analysis of pre-treatment peripheral blood from 10 independent patients with RS treated with anti-PD-1, as well as patients with solid tumors treated with anti-PD-1, supports an association of ZNF683(high) T cells with response.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridg
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, 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. (7) Inserm UMRS1256 Nutrition-Gntique et Exposition Aux Risques Environnementaux (N-GERE), Universit de Lorraine, 54000 Nancy, France; Universit de Lorraine, CHRU-Nancy, Service d'hmatologie Biologique, Ple Laboratoires, 54000 Nancy, France. (8) Inserm UMRS1256 Nutrition-Gntique et Exposition Aux Risques Environnementaux (N-GERE), Universit de Lorraine, 54000 Nancy, France. (9) CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France; EA 7453 (CHELTER), Universit Clermont Auvergne, 63001 Clermont-Ferrand, France. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (12) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (13) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (17) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (18) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA. (20) Department of Hematopoietic Biology and Malignancy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (21) Department of Hematopoietic Biology and Malignancy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (23) Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA. (24) Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. (25) Peter MacCallum Cancer Centre, Royal Melbourne Hospital, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. (26) Alfred Health, Melbourne, VIC, Australia; Monash University, Melbourne, VIC, Australia. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (28) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (29) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (30) Inserm UMRS1256 Nutrition-Gntique et Exposition Aux Risques Environnementaux (N-GERE), Universit de Lorraine, 54000 Nancy, France; Universit de Lorraine, CHRU Nancy, service d'hmatologie clinique, Nancy, France. (31) Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02215, USA. (32) Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. (33) Department of Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (34) Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. (35) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: Catherine_wu@dfci.harvard.edu.
