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 language | English |
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Pages (from-to) | 1803-1816.e8 |
Journal | Cancer Cell |
Volume | 41 |
Issue number | 10 |
DOIs | |
State | Published - 9 Oct 2023 |
Externally published | Yes |
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 .
Funders | Funder number |
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Fishman Family Fund | |
Lavine Family Foundation | R50CA251956, P01 CA206978, 1R01CA155010, 1U10CA180861 |
National Institutes of Health | |
National Cancer Institute | K08 CA270085 |
Doris Duke Charitable Foundation | |
Cancer Prevention and Research Institute of Texas | RR220009 |
Keywords
- Hobit
- PD-1
- Richter transformation
- ZNF683
- checkpoint blockade
- chronic lymphocytic leukemia
- immunotherapy
- single-cell RNA sequencing
- t cells
- tox