Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

Chun Pu Lin; Pierre L. Levy; Astrid Alflen; Georgi Apriamashvili; Maarten A. Ligtenberg; David W. Vredevoogd; Onno B. Bleijerveld; Ferhat Alkan; Yuval Malka; Liesbeth Hoekman; Ettai Markovits; Austin George; Joleen J.H. Traets; Oscar Krijgsman; Alex van Vliet; Joanna Poźniak; Carlos Ariel Pulido-Vicuña; Beaunelle de Bruijn; Susan E. van Hal-van Veen; Julia Boshuizen; Pim W. van der Helm; Judit Díaz-Gómez; Hamdy Warda; Leonie M. Behrens; Paula Mardesic; Bilal Dehni; Nils L. Visser; Jean Christophe Marine; Gal Markel; William J. Faller; Maarten Altelaar; Reuven Agami; Michal J. Besser; Daniel S. Peeper

doi:10.1016/j.ccell.2024.02.016

Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

Chun Pu Lin, Pierre L. Levy, Astrid Alflen, Georgi Apriamashvili, Maarten A. Ligtenberg, David W. Vredevoogd, Onno B. Bleijerveld, Ferhat Alkan, Yuval Malka, Liesbeth Hoekman, Ettai Markovits, Austin George, Joleen J.H. Traets, Oscar Krijgsman, Alex van Vliet, Joanna Poźniak, Carlos Ariel Pulido-Vicuña, Beaunelle de Bruijn, Susan E. van Hal-van Veen, Julia BoshuizenPim W. van der Helm, Judit Díaz-Gómez, Hamdy Warda, Leonie M. Behrens, Paula Mardesic, Bilal Dehni, Nils L. Visser, Jean Christophe Marine, Gal Markel, William J. Faller, Maarten Altelaar, Reuven Agami, Michal J. Besser, Daniel S. Peeper^*

^*Corresponding author for this work

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

1 Scopus citations

Abstract

Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity.

Original language	English
Pages (from-to)	623-645.e10
Journal	Cancer Cell
Volume	42
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2024.02.016
State	Published - 8 Apr 2024

Funding

Funders	Funder number
Dutch Cancer Society KWF
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Oncode Institute
Ministerie van Volksgezondheid, Welzijn en Sport
Netherlands Cancer Institute
X-Omics Initiative	184.034.019
KWF Kankerbestrijding	NKI 2015-7595
KWF Kankerbestrijding
Deutsche Forschungsgemeinschaft	AL2295/1-2, AL2295/1-1
Deutsche Forschungsgemeinschaft
European Commission	101054465
European Commission

Keywords

CRISPR-Cas9 screen
Ctbp1
Dap5
Icam1
T cells
activation-induced cell death
cancer immunotherapy
dysfunction
effector function
exhaustion

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10.1016/j.ccell.2024.02.016

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Lin, C. P., Levy, P. L., Alflen, A., Apriamashvili, G., Ligtenberg, M. A., Vredevoogd, D. W., Bleijerveld, O. B., Alkan, F., Malka, Y., Hoekman, L., Markovits, E., George, A., Traets, J. J. H., Krijgsman, O., van Vliet, A., Poźniak, J., Pulido-Vicuña, C. A., de Bruijn, B., van Hal-van Veen, S. E., ... Peeper, D. S. (2024). Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness. Cancer Cell, 42(4), 623-645.e10. https://doi.org/10.1016/j.ccell.2024.02.016

@article{678d25ee5e31422f8bd38cb327e5c062,

title = "Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness",

abstract = "Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity.",

keywords = "CRISPR-Cas9 screen, Ctbp1, Dap5, Icam1, T cells, activation-induced cell death, cancer immunotherapy, dysfunction, effector function, exhaustion",

author = "Lin, {Chun Pu} and Levy, {Pierre L.} and Astrid Alflen and Georgi Apriamashvili and Ligtenberg, {Maarten A.} and Vredevoogd, {David W.} and Bleijerveld, {Onno B.} and Ferhat Alkan and Yuval Malka and Liesbeth Hoekman and Ettai Markovits and Austin George and Traets, {Joleen J.H.} and Oscar Krijgsman and {van Vliet}, Alex and Joanna Po{\'z}niak and Pulido-Vicu{\~n}a, {Carlos Ariel} and {de Bruijn}, Beaunelle and {van Hal-van Veen}, {Susan E.} and Julia Boshuizen and {van der Helm}, {Pim W.} and Judit D{\'i}az-G{\'o}mez and Hamdy Warda and Behrens, {Leonie M.} and Paula Mardesic and Bilal Dehni and Visser, {Nils L.} and Marine, {Jean Christophe} and Gal Markel and Faller, {William J.} and Maarten Altelaar and Reuven Agami and Besser, {Michal J.} and Peeper, {Daniel S.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = apr,

day = "8",

doi = "10.1016/j.ccell.2024.02.016",

language = "אנגלית",

volume = "42",

pages = "623--645.e10",

journal = "Cancer Cell",

issn = "1535-6108",

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Lin, CP, Levy, PL, Alflen, A, Apriamashvili, G, Ligtenberg, MA, Vredevoogd, DW, Bleijerveld, OB, Alkan, F, Malka, Y, Hoekman, L, Markovits, E, George, A, Traets, JJH, Krijgsman, O, van Vliet, A, Poźniak, J, Pulido-Vicuña, CA, de Bruijn, B, van Hal-van Veen, SE, Boshuizen, J, van der Helm, PW, Díaz-Gómez, J, Warda, H, Behrens, LM, Mardesic, P, Dehni, B, Visser, NL, Marine, JC, Markel, G, Faller, WJ, Altelaar, M, Agami, R, Besser, MJ & Peeper, DS 2024, 'Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness', Cancer Cell, vol. 42, no. 4, pp. 623-645.e10. https://doi.org/10.1016/j.ccell.2024.02.016

TY - JOUR

T1 - Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

AU - Lin, Chun Pu

AU - Levy, Pierre L.

AU - Alflen, Astrid

AU - Apriamashvili, Georgi

AU - Ligtenberg, Maarten A.

AU - Vredevoogd, David W.

AU - Bleijerveld, Onno B.

AU - Alkan, Ferhat

AU - Malka, Yuval

AU - Hoekman, Liesbeth

AU - Markovits, Ettai

AU - George, Austin

AU - Traets, Joleen J.H.

AU - Krijgsman, Oscar

AU - van Vliet, Alex

AU - Poźniak, Joanna

AU - Pulido-Vicuña, Carlos Ariel

AU - de Bruijn, Beaunelle

AU - van Hal-van Veen, Susan E.

AU - Boshuizen, Julia

AU - van der Helm, Pim W.

AU - Díaz-Gómez, Judit

AU - Warda, Hamdy

AU - Behrens, Leonie M.

AU - Mardesic, Paula

AU - Dehni, Bilal

AU - Visser, Nils L.

AU - Marine, Jean Christophe

AU - Markel, Gal

AU - Faller, William J.

AU - Altelaar, Maarten

AU - Agami, Reuven

AU - Besser, Michal J.

AU - Peeper, Daniel S.

PY - 2024/4/8

Y1 - 2024/4/8

N2 - Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity.

AB - Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity.

KW - CRISPR-Cas9 screen

KW - Ctbp1

KW - Dap5

KW - Icam1

KW - T cells

KW - activation-induced cell death

KW - cancer immunotherapy

KW - dysfunction

KW - effector function

KW - exhaustion

UR - http://www.scopus.com/inward/record.url?scp=85187980258&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2024.02.016

DO - 10.1016/j.ccell.2024.02.016

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C2 - 38490212

AN - SCOPUS:85187980258

SN - 1535-6108

VL - 42

SP - 623-645.e10

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

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