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

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 journal › Article › peer-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 ZNF683^high T cells with response.

Original language	English (US)
Pages (from-to)	1803-1816.e8
Journal	Cancer cell
Volume	41
Issue number	10
DOIs	https://doi.org/10.1016/j.ccell.2023.08.013
State	Published - Oct 9 2023

Keywords

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

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.ccell.2023.08.013

Cite this

Parry, E. M., Lemvigh, C. K., Deng, S., Dangle, N., Ruthen, N., Knisbacher, B. A., Broséus, J., Hergalant, S., Guièze, R., Li, S., Zhang, W., Johnson, C., Long, J. M., Yin, S., Werner, L., Anandappa, A., Purroy, N., Gohil, S., Oliveira, G., ... Wu, C. J. (2023). ZNF683 marks a CD8⁺ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome. Cancer cell, 41(10), 1803-1816.e8. https://doi.org/10.1016/j.ccell.2023.08.013

Parry, EM, Lemvigh, CK, Deng, S, Dangle, N, Ruthen, N, Knisbacher, BA, Broséus, J, Hergalant, S, Guièze, R, Li, S, Zhang, W, Johnson, C, Long, JM, Yin, S, Werner, L, Anandappa, A, Purroy, N, Gohil, S, Oliveira, G, Bachireddy, P , Shukla, SA, Huang, T, Khoury, JD, Thakral, B, Dickinson, M, Tam, C, Livak, KJ, Getz, G, Neuberg, D, Feugier, P, Kharchenko, P, Wierda, W, Olsen, LR, Jain, N & Wu, CJ 2023, 'ZNF683 marks a CD8⁺ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome', Cancer cell, vol. 41, no. 10, pp. 1803-1816.e8. https://doi.org/10.1016/j.ccell.2023.08.013

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

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.",

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

author = "Parry, {Erin M.} and Lemvigh, {Camilla K.} and Stephanie Deng and Nathan Dangle and Neil Ruthen and Knisbacher, {Binyamin A.} and Julien Bros{\'e}us and S{\'e}bastien Hergalant and Romain Gui{\`e}ze and Shuqiang Li and Wandi Zhang and Connor Johnson and Long, {Jaclyn M.} and Shanye Yin and Lillian Werner and Annabelle Anandappa and Noelia Purroy and Satyen Gohil and Giacomo Oliveira and Pavan Bachireddy and Shukla, {Sachet A.} and Teddy Huang and Khoury, {Joseph D.} and Beenu Thakral and Michael Dickinson and Constantine Tam and Livak, {Kenneth J.} and Gad Getz and Donna Neuberg and Pierre Feugier and Peter Kharchenko and William Wierda and Olsen, {Lars R{\o}nn} and Nitin Jain and Wu, {Catherine J.}",

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doi = "10.1016/j.ccell.2023.08.013",

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T1 - ZNF683 marks a CD8+ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome

AU - Parry, Erin M.

AU - Lemvigh, Camilla K.

AU - Deng, Stephanie

AU - Dangle, Nathan

AU - Ruthen, Neil

AU - Knisbacher, Binyamin A.

AU - Broséus, Julien

AU - Hergalant, Sébastien

AU - Guièze, Romain

AU - Li, Shuqiang

AU - Zhang, Wandi

AU - Johnson, Connor

AU - Long, Jaclyn M.

AU - Yin, Shanye

AU - Werner, Lillian

AU - Anandappa, Annabelle

AU - Purroy, Noelia

AU - Gohil, Satyen

AU - Oliveira, Giacomo

AU - Bachireddy, Pavan

AU - Shukla, Sachet A.

AU - Huang, Teddy

AU - Khoury, Joseph D.

AU - Thakral, Beenu

AU - Dickinson, Michael

AU - Tam, Constantine

AU - Livak, Kenneth J.

AU - Getz, Gad

AU - Neuberg, Donna

AU - Feugier, Pierre

AU - Kharchenko, Peter

AU - Wierda, William

AU - Olsen, Lars Rønn

AU - Jain, Nitin

AU - Wu, Catherine J.

PY - 2023/10/9

Y1 - 2023/10/9

N2 - 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.

AB - 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.

KW - checkpoint blockade

KW - chronic lymphocytic leukemia

KW - Hobit

KW - immunotherapy

KW - PD-1

KW - Richter transformation

KW - single-cell RNA sequencing

KW - t cells

KW - tox

KW - ZNF683

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U2 - 10.1016/j.ccell.2023.08.013

DO - 10.1016/j.ccell.2023.08.013

M3 - Article

C2 - 37738974

AN - SCOPUS:85173134668

SN - 1535-6108

VL - 41

SP - 1803-1816.e8

JO - Cancer cell

JF - Cancer cell

IS - 10

ER -