Tetracyclines enhance antitumor T-cell immunity via the Zap70 signaling pathway.

Drug Evaluation, Preclinical Non-Small Cell Lung Cancer T-Lymphocytes

Journal

Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585

Informations de publication

Date de publication:
15 Apr 2024
Historique:
accepted: 18 03 2024
medline: 16 4 2024
pubmed: 16 4 2024
entrez: 15 4 2024
Statut: epublish

Résumé

Cancer immunotherapy including immune checkpoint inhibitors is only effective for a limited population of patients with cancer. Therefore, the development of novel cancer immunotherapy is anticipated. In preliminary studies, we demonstrated that tetracyclines enhanced T-cell responses. Therefore, we herein investigated the efficacy of tetracyclines on antitumor T-cell responses by human peripheral T cells, murine models, and the lung tumor tissues of patients with non-small cell lung cancer (NSCLC), with a focus on signaling pathways in T cells. The cytotoxicity of peripheral and lung tumor-infiltrated human T cells against tumor cells was assessed by using bispecific T-cell engager (BiTE) technology (BiTE-assay system). The effects of tetracyclines on T cells in the peripheral blood of healthy donors and the tumor tissues of patients with NSCLC were examined using the BiTE-assay system in comparison with anti-programmed cell death-1 (PD-1) antibody, nivolumab. T-cell signaling molecules were analyzed by flow cytometry, ELISA, and qRT-PCR. To investigate the in vivo antitumor effects of tetracyclines, tetracyclines were administered orally to BALB/c mice engrafted with murine tumor cell lines, either in the presence or absence of anti-mouse CD8 inhibitors. The results obtained revealed that tetracyclines enhanced antitumor T-cell cytotoxicity with the upregulation of granzyme B and increased secretion of interferon-γ in human peripheral T cells and the lung tumor tissues of patients with NSCLC. The analysis of T-cell signaling showed that CD69 in both CD4 In conclusion, tetracyclines enhanced antitumor T-cell immunity via Zap70 signaling. These results will contribute to the development of novel cancer immunotherapy.

Sections du résumé

BACKGROUND BACKGROUND
Cancer immunotherapy including immune checkpoint inhibitors is only effective for a limited population of patients with cancer. Therefore, the development of novel cancer immunotherapy is anticipated. In preliminary studies, we demonstrated that tetracyclines enhanced T-cell responses. Therefore, we herein investigated the efficacy of tetracyclines on antitumor T-cell responses by human peripheral T cells, murine models, and the lung tumor tissues of patients with non-small cell lung cancer (NSCLC), with a focus on signaling pathways in T cells.
METHODS METHODS
The cytotoxicity of peripheral and lung tumor-infiltrated human T cells against tumor cells was assessed by using bispecific T-cell engager (BiTE) technology (BiTE-assay system). The effects of tetracyclines on T cells in the peripheral blood of healthy donors and the tumor tissues of patients with NSCLC were examined using the BiTE-assay system in comparison with anti-programmed cell death-1 (PD-1) antibody, nivolumab. T-cell signaling molecules were analyzed by flow cytometry, ELISA, and qRT-PCR. To investigate the in vivo antitumor effects of tetracyclines, tetracyclines were administered orally to BALB/c mice engrafted with murine tumor cell lines, either in the presence or absence of anti-mouse CD8 inhibitors.
RESULTS RESULTS
The results obtained revealed that tetracyclines enhanced antitumor T-cell cytotoxicity with the upregulation of granzyme B and increased secretion of interferon-γ in human peripheral T cells and the lung tumor tissues of patients with NSCLC. The analysis of T-cell signaling showed that CD69 in both CD4
CONCLUSIONS CONCLUSIONS
In conclusion, tetracyclines enhanced antitumor T-cell immunity via Zap70 signaling. These results will contribute to the development of novel cancer immunotherapy.

Identifiants

DOI: 10.1136/jitc-2023-008334 PMID: 38621815
pubmed: 38621815
pii: jitc-2023-008334
doi: 10.1136/jitc-2023-008334
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: There are no competing interests.

Auteurs

Mari Tone (M)

Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.

Kota Iwahori (K)

Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan iwahori@climm.med.osaka-u.ac.jp.
Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
ORCID: 0000-0002-9891-6003

Michinari Hirata (M)

Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Biopharmaceutical Research Division, Shionogi & Co., Ltd, Osaka, Japan.

Azumi Ueyama (A)

Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Biopharmaceutical Research Division, Shionogi & Co., Ltd, Osaka, Japan.

Akiyoshi Tani (A)

Compound Library Screening Center, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

Jun-Ichi Haruta (JI)

Lead Explorating Units, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

Yoshito Takeda (Y)

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.

Yasushi Shintani (Y)

Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.

Atsushi Kumanogoh (A)

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan.
Center for Infectious Diseases for Education and Research (CiDER), Osaka University, Osaka, Japan.
Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Osaka University, Osaka, Japan.
Center for Advanced Modalities and DDS (CAMaD), Osaka University, Osaka, Japan.

Hisashi Wada (H)

Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.

Classifications MeSH