ZNF683 marks a CD8+ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome

Erin M Parry; Camilla K Lemvigh; Stephanie Deng; Nathan Dangle; Neil Ruthen; Binyamin A Knisbacher; Julien Broséus; Sébastien Hergalant; Romain Guièze; Shuqiang Li; Wandi Zhang; Connor Johnson; Jaclyn M Long; Shanye Yin; Lillian Werner; Annabelle Anandappa; Noelia Purroy; Satyen Gohil; Giacomo Oliveira; Pavan Bachireddy; Sachet A Shukla; Teddy Huang; Joseph D Khoury; Beenu Thakral; Michael Dickinson; Constantine Tam; Kenneth J Livak; Gad Getz; Donna Neuberg; Pierre Feugier; Peter Kharchenko; William Wierda; Lars Rønn Olsen; Nitin Jain; Catherine J Wu

doi:10.1016/j.ccell.2023.08.013

ZNF683 marks a CD8⁺ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome

Cancer Cell. 2023 Oct 9;41(10):1803-1816.e8. doi: 10.1016/j.ccell.2023.08.013. Epub 2023 Sep 21.

Authors

Erin M Parry¹, Camilla K Lemvigh², Stephanie Deng³, Nathan Dangle³, Neil Ruthen³, Binyamin A Knisbacher⁴, Julien Broséus⁵, Sébastien Hergalant⁶, Romain Guièze⁷, Shuqiang Li⁸, Wandi Zhang³, Connor Johnson⁴, Jaclyn M Long⁹, Shanye Yin³, Lillian Werner¹⁰, Annabelle Anandappa³, Noelia Purroy³, Satyen Gohil³, Giacomo Oliveira¹¹, Pavan Bachireddy¹², Sachet A Shukla¹², Teddy Huang¹³, Joseph D Khoury¹⁴, Beenu Thakral¹⁵, Michael Dickinson¹⁶, Constantine Tam¹⁷, Kenneth J Livak¹³, Gad Getz⁴, Donna Neuberg¹⁰, Pierre Feugier¹⁸, Peter Kharchenko¹⁹, William Wierda²⁰, Lars Rønn Olsen²¹, Nitin Jain²⁰, Catherine J Wu²²

Affiliations

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 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Inserm UMRS1256 Nutrition-Génétique et Exposition Aux Risques Environnementaux (N-GERE), Université de Lorraine, 54000 Nancy, France; Université de Lorraine, CHRU-Nancy, Service d'hématologie Biologique, Pôle Laboratoires, 54000 Nancy, France.
⁶ Inserm UMRS1256 Nutrition-Génétique et Exposition Aux Risques Environnementaux (N-GERE), Université de Lorraine, 54000 Nancy, France.
⁷ CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France; EA 7453 (CHELTER), Université Clermont Auvergne, 63001 Clermont-Ferrand, France.
⁸ 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.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; 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.
¹⁰ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Hematopoietic Biology and Malignancy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁴ Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁵ Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
¹⁶ Peter MacCallum Cancer Centre, Royal Melbourne Hospital, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
¹⁷ Alfred Health, Melbourne, VIC, Australia; Monash University, Melbourne, VIC, Australia.
¹⁸ Inserm UMRS1256 Nutrition-Génétique et Exposition Aux Risques Environnementaux (N-GERE), Université de Lorraine, 54000 Nancy, France; Université de Lorraine, CHRU Nancy, service d'hématologie clinique, Nancy, France.
¹⁹ Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02215, USA.
²⁰ Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
²¹ Department of Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark.
²² 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: [email protected].

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.

Keywords: Hobit; PD-1; Richter transformation; ZNF683; checkpoint blockade; chronic lymphocytic leukemia; immunotherapy; single-cell RNA sequencing; t cells; tox.

Publication types

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

MeSH terms

CD8-Positive T-Lymphocytes
Gene Expression Regulation
Humans
Immunotherapy
Leukemia, Lymphocytic, Chronic, B-Cell* / pathology
Lymphoma, Large B-Cell, Diffuse* / drug therapy
Lymphoma, Large B-Cell, Diffuse* / genetics
Lymphoma, Large B-Cell, Diffuse* / pathology

Abstract

Publication types

MeSH terms

Grants and funding