Induction of the activating transcription factor-4 in the intratumoral CD8+ T cells sustains their viability and anti-tumor activities

Zhen Lu; Eun-Ah Bae; Ioannis I Verginadis; Hongru Zhang; Christina Cho; Noreen McBrearty; Subin S George; J Alan Diehl; Constantinos Koumenis; Linda M Bradley; Serge Y Fuchs

doi:10.1007/s00262-022-03286-2

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Induction of the activating transcription factor-4 in the intratumoral CD8+ T cells sustains their viability and anti-tumor activities

Journal article

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Peer reviewed

Induction of the activating transcription factor-4 in the intratumoral CD8+ T cells sustains their viability and anti-tumor activities

Zhen Lu, Eun-Ah Bae, Ioannis I Verginadis, Hongru Zhang, Christina Cho, Noreen McBrearty, Subin S George, J Alan Diehl, Constantinos Koumenis, Linda M Bradley, …

Cancer immunology, immunotherapy, Vol.72(4), pp.815-826

04/01/2023

DOI: 10.1007/s00262-022-03286-2

PMCID: PMC10317204

PMID: 36063172

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Abstract

Immune suppressive factors of the tumor microenvironment (TME) undermine viability and exhaust the activities of the intratumoral cytotoxic CD8 + T lymphocytes (CTL) thereby evading anti-tumor immunity and decreasing the benefits of immune therapies. To counteract this suppression and improve the efficacy of therapeutic regimens, it is important to identify and understand the critical regulators within CD8 + T cells that respond to TME stress and tumor-derived factors. Here we investigated the regulation and importance of activating transcription factor-4 (ATF4) in CTL using a novel Atf4 mouse model lacking ATF4 specifically in CD8 + cells. Induction of ATF4 in CD8 + T cells occurred in response to antigenic stimulation and was further increased by exposure to tumor-derived factors and TME conditions. Under these conditions, ATF4 played a critical role in the maintenance of survival and activities of CD8 + T cells. Conversely, selective ablation of ATF4 in CD8 + T cells in mice rendered these Atf4 hosts prone to accelerated growth of implanted tumors. Intratumoral ATF4-deficient CD8 + T cells were under-represented compared to wild-type counterparts and exhibited impaired activation and increased apoptosis. These findings identify ATF4 as an important regulator of viability and activity of CD8 + T cells in the TME and argue for caution in using agents that could undermine these functions of ATF4 for anti-cancer therapies.

Activating Transcription Factors

Animals

CD8-Positive T-Lymphocytes

Lymphocytes, Tumor-Infiltrating

Mice

Neoplasms

T-Lymphocytes, Cytotoxic

Tumor Microenvironment

Details

Title: Subtitle: Induction of the activating transcription factor-4 in the intratumoral CD8+ T cells sustains their viability and anti-tumor activities
Creators: Zhen Lu - University of Pennsylvania
Eun-Ah Bae - Sanford Burnham Prebys Medical Discovery Institute
Ioannis I Verginadis - University of Pennsylvania
Hongru Zhang - University of Pennsylvania
Christina Cho - University of Pennsylvania
Noreen McBrearty - University of Pennsylvania
Subin S George - University of Pennsylvania
J Alan Diehl - Case Western Reserve University
Constantinos Koumenis - University of Pennsylvania
Linda M Bradley - Sanford Burnham Prebys Medical Discovery Institute
Serge Y Fuchs - University of Pennsylvania
Resource Type: Journal article
Publication Details: Cancer immunology, immunotherapy, Vol.72(4), pp.815-826
DOI: 10.1007/s00262-022-03286-2
PMID: 36063172
PMCID: PMC10317204
NLM abbreviation: Cancer Immunol Immunother
ISSN: 0340-7004
eISSN: 1432-0851
Grant note: P01 CA165997 / NCI NIH HHS CA165997 / NCI NIH HHS T32 CA115299 / NCI NIH HHS CA115299 / NCI NIH HHS CA216187 / NCI NIH HHS CA240814 / NCI NIH HHS R01 CA240814 / NCI NIH HHS R01 CA216187 / NCI NIH HHS
Language: English
Date published: 04/01/2023
Academic Unit: Internal Medicine
Record Identifier: 9984949216702771

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