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 BachireddySachet 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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 ZNF683high T cells with response.

Original languageEnglish
Pages (from-to)1803-1816.e8
JournalCancer Cell
Volume41
Issue number10
DOIs
StatePublished - 9 Oct 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Funding

We are grateful to Lucas Pomerance, Catherine Gutierrez, Cleo Forman, Cynthia Hahn, Ignaty Leshchiner and David Braun for constructive and valuable discussion and for Jennifer Brown, Stacey Fernandes, Philippe Armand, Stephan Stilgenbauer, Eugen Tausch, Barbara Eichhorst and Othman Al-Sawaf for helpful conversations. We acknowledge Samantha Hoffman for helpful input. We appreciate Elizabeth Witten for expert lab management, Fanny Dao for data management and Joyce Breaker for sample management. E.M.P. acknowledges support from the Doris Duke Charitable Foundation ( Physician-Scientist Fellowship ), the Dana-Farber FLAMES Lymphoma Fellowship , and NIH/NCI K08 CA270085 . C.K.L is supported in part by the Fishman Family Fund . C.J.W. acknowledges support from the Lavine Family Foundation . S.L. is supported by the NCI Research Specialist Award ( R50CA251956 ). The authors acknowledge the Centre de Ressources Biologiques (CRB) Lorrain of Nancy BB-0033-00035 for patient sample management and the French Innovative Leukemia Organization (FILO). This study was supported by NIH/NCI P01 CA206978 (to C.J.W. and G.G.) and NCI ( 1U10CA180861 and 1R01CA155010 ) (to C.J.W). S.A.S. is supported by CPRIT RR220009 .

FundersFunder number
Fishman Family Fund
Lavine Family FoundationR50CA251956, P01 CA206978, 1R01CA155010, 1U10CA180861
National Institutes of Health
National Cancer InstituteK08 CA270085
Doris Duke Charitable Foundation
Cancer Prevention and Research Institute of TexasRR220009

    Keywords

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

    Fingerprint

    Dive into the research topics of 'ZNF683 marks a CD8+ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome'. Together they form a unique fingerprint.

    Cite this