Interferon-γ in the tumor microenvironment promotes the expression of B7H4 in colorectal cancer cells, thereby inhibiting cytotoxic T cells

Jing, Zhi-liang; Liu, Guang-long; Zhou, Na; Xu, Dong-yan; Feng, Na; Lei, Yan; Ma, Li-li; Tang, Min-shan; Tong, Gui-hui; Tang, Na; Deng, Yong-jian

doi:10.1038/s41598-024-56681-3

Cited by 3 publications

(2 citation statements)

References 45 publications

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“…B7H4 is involved in tumour immunosuppressive mechanisms and is a checkpoint for inhibition [58]. Besides the prognostic value of B7H4, after PD-L1/PD-1 and CTLA-4, it is expected to be another ICB (immune checkpoint blockage) target [59].…”

Section: Discussionmentioning

confidence: 99%

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Prognostic Value of B7H4 Expression in Patients with Solid Cancers: A Systematic Review and Meta-Analysis

Dawidowicz,

Kula,

Mielcarska

et al. 2024

IJMS

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V-set domain-containing T-cell activation inhibitor 1 (aliases VTCN1, B7H4) participates in tumour immune escape by delivering inhibitory signals to T cells. The purpose of this article was to assess the B7H4 prognostic value in solid cancers. Three databases were searched for relevant articles. The main endpoints were overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), recurrence-free survival (RFS), and disease-free survival (DFS). Appropriate hazard ratios (HRs) were pooled. The R studio software (version 4.0.3) was used for data analysis. Thirty-one studies met the inclusion criteria. High expression of B7H4 was associated with worse OS (HR = 1.52, 95% CI: 1.37–1.68) but not with DSS (HR = 1.14, 95% CI: 0.49–2.63), RFS (HR = 1.77, 95% CI: 0.75–4.18), DFS (HR = 1.29, 95% CI: 0.8–2.09), or PFS (HR = 1.71, 95% CI: 0.91–3.2) in patients with solid cancers. High expression of B7H4 is associated with a poorer prognosis in patients with solid cancers. B7H4 is a promising prognostic biomarker and immunotherapeutic target for various solid cancers because of its activity in cancer immunity and tumourigenesis.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, high expression of B7H4 is related to low infiltration levels of cytotoxic T lymphocytes [58,62]. The inhibition of B7H4 glycosylation has been reported to restore antitumour immunity in immune cold breast cancers [26].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of B7H4 Expression in Patients with Solid Cancers: A Systematic Review and Meta-Analysis

Dawidowicz,

Kula,

Mielcarska

et al. 2024

IJMS

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The Aryl Hydrocarbon Receptor Controls IFNγ-Induced Immune Checkpoints PD-L1 and IDO via the JAK/STAT Pathway in Lung Adenocarcinoma

Snyder,

Wang,

Lara

et al. 2024

Preprint

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While immunotherapy has shown efficacy in lung adenocarcinoma (LUAD) patients, many respond only partially or not at all. One limitation in improving outcomes is the lack of a complete understanding of immune checkpoint regulation. Here, we investigated a possible link between an environmental chemical receptor implicated in lung cancer and immune regulation,(the aryl hydrocarbon receptor/AhR), a known but counterintuitive mediator of immunosuppression (IFNγ), and regulation of two immune checkpoints (PD-L1 and IDO). AhR gene-edited LUAD cell lines, a syngeneic LUAD mouse model, bulk- and scRNA sequencing of LUADs and tumor-infiltrating leukocytes were used to map out a signaling pathway leading from IFNγ through the AhR to JAK/STAT, PD-L1, IDO, and tumor-mediated immunosuppression. The data demonstrate that:1)IFNγ activation of the JAK/STAT pathway leading to PD-L1 and IDO1 upregulation is mediated by the AhR in murine and human LUAD cells,2)AhR-driven IDO1 induction results in the production of Kynurenine (Kyn), an AhR ligand, which likely mediates an AhR➔IDO1➔Kyn➔AhR amplification loop,3)transplantation of AhR-knockout LUAD cells results in long-term tumor immunity in most recipients.4)The 23% of AhR-knockout tumors that do grow do so at a much slower pace than controls and exhibit higher densities of CD8+T cells expressing markers of immunocompetence, increased activity, and increased cell-cell communication. The data definitively link the AhR to IFNγ-induced JAK/STAT pathway and immune checkpoint-mediated immunosuppression and support the targeting of the AhR in the context of LUAD.

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B7H4 Role in Solid Cancers: A Review of the Literature

Dawidowicz,

Kot,

Mielcarska

et al. 2024

Cancers

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Anti-cancer immunotherapies entirely changed the therapeutic approach to oncological patients. However, despite the undeniable success of anti-PD-1, PD-L1, and CTLA-4 antibody treatments, their effectiveness is limited either by certain types of malignancies or by the arising problem of cancer resistance. B7H4 (aliases B7x, B7H4, B7S1, VTCN1) is a member of a B7 immune checkpoint family with a distinct expression pattern from classical immune checkpoint pathways. The growing amount of research results seem to support the thesis that B7H4 might be a very potent therapeutic target. B7H4 was demonstrated to promote tumour progression in immune “cold” tumours by promoting migration, proliferation of tumour cells, and cancer stem cell persistence. B7H4 suppresses T cell effector functions, including inflammatory cytokine production, cytolytic activity, proliferation of T cells, and promoting the polarisation of naïve CD4 T cells into induced Tregs. This review aimed to summarise the available information about B7H4, focusing in particular on clinical implications, immunological mechanisms, potential strategies for malignancy treatment, and ongoing clinical trials.

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Interferon-γ in the tumor microenvironment promotes the expression of B7H4 in colorectal cancer cells, thereby inhibiting cytotoxic T cells

Cited by 3 publications

References 45 publications

Prognostic Value of B7H4 Expression in Patients with Solid Cancers: A Systematic Review and Meta-Analysis

Prognostic Value of B7H4 Expression in Patients with Solid Cancers: A Systematic Review and Meta-Analysis

The Aryl Hydrocarbon Receptor Controls IFNγ-Induced Immune Checkpoints PD-L1 and IDO via the JAK/STAT Pathway in Lung Adenocarcinoma

B7H4 Role in Solid Cancers: A Review of the Literature

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