In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer

Zeyu Chen; Eri Arai; Omar Khan; Zhen Zhang; Shin Foong Ngiow; Yuan He; Hua Huang; Sasikanth Manne; Zhendong Cao; Amy E. Baxter; Zhangying Cai; Elizabeth Freilich; Mohammed A. Ali; Josephine R. Giles; Jennifer E. Wu; Allison R. Greenplate; Mohamed A. Hakeem; Qingzhou Chen; Makoto Kurachi; Kito Nzingha; Viktoriya Ekshyyan; Divij Mathew; Zhuoyu Wen; Nancy A. Speck; Alexis Battle; Shelley L. Berger; E. John Wherry; Junwei Shi

doi:10.1016/j.cell.2021.02.019

In vivo CD8⁺ T cell CRISPR screening reveals control by Fli1 in infection and cancer

Zeyu Chen
, Eri Arai
, Omar Khan
, Zhen Zhang
, Shin Foong Ngiow
, Yuan He
, Hua Huang
, Sasikanth Manne
, Zhendong Cao
, Amy E. Baxter
, Zhangying Cai
, Elizabeth Freilich
, Mohammed A. Ali
, Josephine R. Giles
, Jennifer E. Wu
, Allison R. Greenplate
, Mohamed A. Hakeem
, Qingzhou Chen
, Makoto Kurachi
, Kito Nzingha

Viktoriya Ekshyyan, Divij Mathew, Zhuoyu Wen, Nancy A. Speck, Alexis Battle, Shelley L. Berger, E. John Wherry, Junwei Shi

Krieger School of Arts and Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (T_EFF)-driving transcription factors (TFs), the transcriptional coordination of T_EFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining T_EFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced T_EFF responses without compromising memory or exhaustion precursors. Fli1 restrained T_EFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven T_EFF biology. CD8⁺ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8⁺ T cell transcriptional landscape from excessive ETS:RUNX-driven T_EFF cell differentiation. Moreover, genetic deletion of Fli1 improves T_EFF differentiation and protective immunity in infections and cancer. An in vivo T cell CRISPR screening platform identifies Fli1 as a factor modulating CD8⁺ T cell effector differentiation with limited effects on memory or exhaustion.

Original language	English (US)
Pages (from-to)	1262-1280.e22
Journal	Cell
Volume	184
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2021.02.019
State	Published - Mar 4 2021

Keywords

CD8
CRISPR
Fli1
cancer
chronic infection
effector CD8 T cell
exhausted CD8 T cell
exhaustion
immunotherapy
protective immunity

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2021.02.019

Cite this

Chen, Z., Arai, E., Khan, O., Zhang, Z., Ngiow, S. F., He, Y., Huang, H., Manne, S., Cao, Z., Baxter, A. E., Cai, Z., Freilich, E., Ali, M. A., Giles, J. R., Wu, J. E., Greenplate, A. R., Hakeem, M. A., Chen, Q., Kurachi, M., ... Shi, J. (2021). In vivo CD8⁺ T cell CRISPR screening reveals control by Fli1 in infection and cancer. Cell, 184(5), 1262-1280.e22. https://doi.org/10.1016/j.cell.2021.02.019

Chen, Z, Arai, E, Khan, O, Zhang, Z, Ngiow, SF, He, Y, Huang, H, Manne, S, Cao, Z, Baxter, AE, Cai, Z, Freilich, E, Ali, MA, Giles, JR, Wu, JE, Greenplate, AR, Hakeem, MA, Chen, Q, Kurachi, M, Nzingha, K, Ekshyyan, V, Mathew, D, Wen, Z, Speck, NA, Battle, A, Berger, SL, Wherry, EJ & Shi, J 2021, 'In vivo CD8⁺ T cell CRISPR screening reveals control by Fli1 in infection and cancer', Cell, vol. 184, no. 5, pp. 1262-1280.e22. https://doi.org/10.1016/j.cell.2021.02.019

@article{2df15aab71894c498a0eafccaca02bb8,

title = "In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer",

abstract = "Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TFs), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven TEFF biology. CD8+ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8+ T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer. An in vivo T cell CRISPR screening platform identifies Fli1 as a factor modulating CD8+ T cell effector differentiation with limited effects on memory or exhaustion.",

keywords = "CD8, CRISPR, Fli1, cancer, chronic infection, effector CD8 T cell, exhausted CD8 T cell, exhaustion, immunotherapy, protective immunity",

author = "Zeyu Chen and Eri Arai and Omar Khan and Zhen Zhang and Ngiow, \{Shin Foong\} and Yuan He and Hua Huang and Sasikanth Manne and Zhendong Cao and Baxter, \{Amy E.\} and Zhangying Cai and Elizabeth Freilich and Ali, \{Mohammed A.\} and Giles, \{Josephine R.\} and Wu, \{Jennifer E.\} and Greenplate, \{Allison R.\} and Hakeem, \{Mohamed A.\} and Qingzhou Chen and Makoto Kurachi and Kito Nzingha and Viktoriya Ekshyyan and Divij Mathew and Zhuoyu Wen and Speck, \{Nancy A.\} and Alexis Battle and Berger, \{Shelley L.\} and Wherry, \{E. John\} and Junwei Shi",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = mar,

day = "4",

doi = "10.1016/j.cell.2021.02.019",

language = "English (US)",

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T1 - In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer

AU - Chen, Zeyu

AU - Arai, Eri

AU - Khan, Omar

AU - Zhang, Zhen

AU - Ngiow, Shin Foong

AU - He, Yuan

AU - Huang, Hua

AU - Manne, Sasikanth

AU - Cao, Zhendong

AU - Baxter, Amy E.

AU - Cai, Zhangying

AU - Freilich, Elizabeth

AU - Ali, Mohammed A.

AU - Giles, Josephine R.

AU - Wu, Jennifer E.

AU - Greenplate, Allison R.

AU - Hakeem, Mohamed A.

AU - Chen, Qingzhou

AU - Kurachi, Makoto

AU - Nzingha, Kito

AU - Ekshyyan, Viktoriya

AU - Mathew, Divij

AU - Wen, Zhuoyu

AU - Speck, Nancy A.

AU - Battle, Alexis

AU - Berger, Shelley L.

AU - Wherry, E. John

AU - Shi, Junwei

PY - 2021/3/4

Y1 - 2021/3/4

N2 - Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TFs), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven TEFF biology. CD8+ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8+ T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer. An in vivo T cell CRISPR screening platform identifies Fli1 as a factor modulating CD8+ T cell effector differentiation with limited effects on memory or exhaustion.

AB - Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TFs), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven TEFF biology. CD8+ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8+ T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer. An in vivo T cell CRISPR screening platform identifies Fli1 as a factor modulating CD8+ T cell effector differentiation with limited effects on memory or exhaustion.

KW - CD8

KW - CRISPR

KW - Fli1

KW - cancer

KW - chronic infection

KW - effector CD8 T cell

KW - exhausted CD8 T cell

KW - exhaustion

KW - immunotherapy

KW - protective immunity

UR - https://www.scopus.com/pages/publications/85101760023

UR - https://www.scopus.com/pages/publications/85101760023#tab=citedBy

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DO - 10.1016/j.cell.2021.02.019

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AN - SCOPUS:85101760023

SN - 0092-8674

VL - 184

SP - 1262-1280.e22

JO - Cell

JF - Cell

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ER -