The impact of CCR8+ regulatory T cells on cytotoxic T cell function in human lung cancer

Haruna, Miya; Ueyama, Azumi; Yamamoto, Yoko; Hirata, Michinari; Goto, Kumiko; Yoshida, Hiroshi; Higuchi, Naoko; Yoshida, Tetsuya; Kidani, Yujiro; Nakamura, Yurika; Nagira, Morio; Kawashima, Atsunari; Iwahori, Kota; Shintani, Yasushi; Ohkura, Naganari; Wada, Hisashi

doi:10.1038/s41598-022-09458-5

Cited by 25 publications

(18 citation statements)

References 32 publications

(58 reference statements)

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“…Melanoma antigen recognized by T cells-1 (MART-1) tetramer-positive CD8 + T cells were induced by a co-culture with the MART-1 peptide as described in our previous Open access study. 14 PBMCs from an HLA-02:01-positive donor (Cellular Technology Limited, CLE, Ohio, USA) were co-cultured with 1 µg/mL of the 02;01-MART-1 peptide (Medical & Biological Laboratories, Tokyo, Japan) and 50 U/mL of IL-2 for 14 days. MART-1 tetramer-positive CD8 + T cells were then isolated using MACS Quant Tyto (Miltenyi Biotec) after being stained with CD8a and HLA-A*02:01 MART-1 Tetramer-ELAGIGILTV (Medical & Biological Laboratories).…”

Section: Human Ctl Assaymentioning

confidence: 99%

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

Tone,

Iwahori,

Hirata

et al. 2024

J Immunother Cancer

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BackgroundCancer 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.MethodsThe 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.ResultsThe 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+and CD8+T cells was upregulated by minocycline. Downstream of T-cell receptor signaling, Zap70 phosphorylation and Nur77 were also upregulated by minocycline in the early phase after T-cell activation. These changes were not observed in T cells treated with anti-PD-1 antibodies under the same conditions. The administration of tetracyclines exhibited antitumor efficacy with the upregulation of CD69 and increases in tumor antigen-specific T cells in murine tumor models. These changes were canceled by the administration of anti-mouse CD8 inhibitors.ConclusionsIn conclusion, tetracyclines enhanced antitumor T-cell immunity via Zap70 signaling. These results will contribute to the development of novel cancer immunotherapy.

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Section: Human Ctl Assaymentioning

confidence: 99%

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

Tone,

Iwahori,

Hirata

et al. 2024

J Immunother Cancer

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“…The ligand of CCR8, CCL1, enhances tumor immunosuppressive microenvironment via the recruitment of CCR8 + Treg cells [179]. Anti-CCR8 antibody is able to selectively eliminate the clonally expanding Treg cells within the tumor, but has no effect on tumor-infiltrating effector T cells or natural Treg cells [180][181][182][183][184][185], making it a potential treatment for GIST. In GIST cell lines, KIT exon 11 codon 557-558 deletion enhances the expression of C-X-C chemokine receptor 4 (CXCR4) [186].…”

Section: Other Immune-related Genesmentioning

confidence: 99%

Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers

Chen

Yang

et al. 2023

Mol Cancer

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Mesenchymal gastrointestinal cancers are represented by the gastrointestinal stromal tumors (GISTs) which occur throughout the whole gastrointestinal tract, and affect human health and economy globally. Curative surgical resections and tyrosine kinase inhibitors (TKIs) are the main managements for localized GISTs and recurrent/metastatic GISTs, respectively. Despite multi-lines of TKIs treatments prolonged the survival time of recurrent/metastatic GISTs by delaying the relapse and metastasis of the tumor, drug resistance developed quickly and inevitably, and became the huge obstacle for stopping disease progression. Immunotherapy, which is typically represented by immune checkpoint inhibitors (ICIs), has achieved great success in several solid tumors by reactivating the host immune system, and been proposed as an alternative choice for GIST treatment. Substantial efforts have been devoted to the research of immunology and immunotherapy for GIST, and great achievements have been made. Generally, the intratumoral immune cell level and the immune-related gene expressions are influenced by metastasis status, anatomical locations, driver gene mutations of the tumor, and modulated by imatinib therapy. Systemic inflammatory biomarkers are regarded as prognostic indicators of GIST and closely associated with its clinicopathological features. The efficacy of immunotherapy strategies for GIST has been widely explored in pre-clinical cell and mouse models and clinical experiments in human, and some patients did benefit from ICIs. This review comprehensively summarizes the up-to-date advancements of immunology, immunotherapy and research models for GIST, and provides new insights and perspectives for future studies.

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“…Many cancers, including lung, pancreatic and breast cancer, have been shown to have significant elevation in regulatory T cells. 127,128 The tumor microenvironment (TME) is a metabolite deficient, hypoxic, and acidic environment created by the increased glucose uptake and lactate generation of tumor cells. This makes it possible for invading effector T cells to compete with the tumor for metabolites, altering their ability to proliferate and function.…”

Section: Cells (T-regs) and Naturally Occurring Natural Regulatory T ...mentioning

confidence: 99%

“…Many cancers, including lung, pancreatic and breast cancer, have been shown to have significant elevation in regulatory T cells. 127,128…”

Section: Applications Of Supramolecular Immunotherapy To Diverse Immu...mentioning

confidence: 99%

Supramolecular immunotherapy on diversiform immune cells

Wang¹,

Zhang²,

Chen³

2023

J. Mater. Chem. B

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The impact of CCR8+ regulatory T cells on cytotoxic T cell function in human lung cancer

Cited by 25 publications

References 32 publications

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

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

Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers

Supramolecular immunotherapy on diversiform immune cells

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