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 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

14 Citations (Scopus)

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
Number of pages	34
Journal	Cancer Cell
Volume	42
Issue number	4
Early online date	14 Mar 2024
DOIs	https://doi.org/10.1016/j.ccell.2024.02.016
Publication status	Published - 8 Apr 2024

Bibliographical note

Keywords

Humans
CRISPR-Cas Systems
CD8-Positive T-Lymphocytes
Neoplasms/genetics

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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{85fb7746beef406a9b5187252e129d5d,

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 = "Humans, CRISPR-Cas Systems, CD8-Positive T-Lymphocytes, Neoplasms/genetics",

author = "Chun-Pu Lin 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 Jean-Christophe Marine and Gal Markel and Faller, \{William J\} and Maarten Altelaar and Reuven Agami and Besser, \{Michal J\} and Peeper, \{Daniel S\}",

year = "2024",

month = apr,

day = "8",

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

language = "English",

volume = "42",

pages = "623--645.e10",

journal = "Cancer Cell",

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Lin, C-P, 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, J-C, 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 - Humans

KW - CRISPR-Cas Systems

KW - CD8-Positive T-Lymphocytes

KW - Neoplasms/genetics

UR - http://europepmc.org/abstract/med/38490212

U2 - 10.1016/j.ccell.2024.02.016

DO - 10.1016/j.ccell.2024.02.016

M3 - Article (Academic Journal)

C2 - 38490212

SN - 1535-6108

VL - 42

SP - 623-645.e10

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -