The B7H4-PDL1 classifier stratifies immuno-phenotype in cervical cancer

Chen, Lingyan; Dong, Jianfeng; Zhu, Yichao; Chen, Yu; Zhang, Yan

doi:10.1186/s12935-021-02423-8

Cited by 5 publications

(3 citation statements)

References 44 publications

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“…Moreover, the expression of PD-L1 also increased. This seems to contradict our ideal result [27,28] . Currently, monoclonal antibodies that block the interaction between PD-1 and PD-L1 by binding to ligands or receptors have shown signi cant clinical e cacy in patients with a variety of cancers [29,30] .…”

Section: Discussioncontrasting

confidence: 74%

KDM6B enhances anti-PD-L1 immunotherapy efficacy by increasing CD8+ T-cell infiltration in colorectal cancer

Xun,

Liu,

Liu

et al. 2024

Preprint

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Background: CD8+ T cells in the tumor microenvironment are crucial for antitumor effects. Boosting their infiltration can significantly enhance the efficacy of antitumor immunotherapy. However, the precise contribution of the epigenetic regulator lysine-specific demethylase 6B (KDM6B) to colorectal cancer (CRC) immunity remains elusive. Methods: KDM6B expression was detected in adjacent and CRC tissues or normal and cancer cells. Mouse models of CRC were established to assess the impact of KDM6B on tumor progression. The infiltration of CD8+ T cells was detected by IHC and a transwell assay. RT-qPCR, western blotting or flow cytometry were used to detect the effect of KDM6B on PD-L1, CD8+ T-cell-attracting chemokines and p-STAT3 expression. ChIP-qPCR was performed to determine the H3K27me3 enrichment in the promoter regions of target genes PD-L1 and CD8+ T-cell-attracting chemokines. Finally, paricalcitol was combined with anti-PD-L1 antibodies to evaluate their anti-CRC effects. Results: KDM6B was downregulated in CRC tissues and cells, but its overexpression successfully hindered CRC growth and liver metastasis. Mechanistically, the activation of demethylase activity and STAT3 signaling, leading to increased expression of CD8+ T-cell-attracting chemokines CCL5, CXCL9, and CXCL10, as well as enhanced PD-L1 expression in CRC cells. This ultimately resulted in increased infiltration of CD8+ T cells. Paricalcitol and anti-PD-L1 antibody therapy work together to achieve superior tumor elimination efficiency. Paricalcitol, combined with anti-PD-L1 antibodies, offered superior tumor elimination efficiency. Conclusion: These findings suggest that KDM6B plays a positive role in regulating the immune microenvironment in CRC, potentially offering a theoretical basis for CRC immunotherapy.

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Section: Discussioncontrasting

confidence: 74%

KDM6B enhances anti-PD-L1 immunotherapy efficacy by increasing CD8+ T-cell infiltration in colorectal cancer

Xun,

Liu,

Liu

et al. 2024

Preprint

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“…Increasing numbers of research have uncovered that B7-H4 and B7-H5 were abnormally expressed in a variety of human malignant tumor tissues and correlated with disease prognosis [ 12 , 16 , 17 ]. In this study, it was found that B7-H4 and B7-H5 gene expression levels were down-regulated in keratinocytes cell lines of CSCC, and correlated with tumor staging.…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of B7-H4 and B7-H5 contributes to the development of cutaneous squamous cell carcinoma

Chen,

Zhou,

Tang

et al. 2024

Arch Dermatol Res

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Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant tumor of the skin. B7 homolog 4 (B7-H4) and B7-H5 (B7 homolog 5) are associated with a variety of tumors. Investigate the potential role of B7-H4 and B7-H5 in regulating the tumorigenesis and progression of CSCC. B7-H4 and B7-H5 transcriptome data were collected from GEO and TCGA databases and subjected to bioinformatical analysis by protein–protein interaction (PPI) network, functional enrichment analysis, immune analysis, and drug–gene interaction prediction analysis. We characterized the expression of B7-H4 and B7-H5 in carcinoma tissues of CSCC patients by immunohistochemistry. Meanwhile, the clinical correlation of B7-H4 and B7-H5 in CSCC was explored by statistical analysis. B7-H4 and B7-H5 genes were under-expressed in CSCC and correlated with tumor staging. According to GO and KEGG Pathway enrichment analysis, B7-H4, and B7-H5 can regulate the proliferation and activation of T cells, lymphocytes, and monocytes, and the expression of cytokines, such as IL-6 and IL-10, in CSCC. B7-H4 and B7-H5 are also jointly involved in the occurrence and development of CSCC via the JAK-STAT and Notch signaling pathways. We found that B7-H4 and B7-H5 proteins were abnormally highly expressed in CSCC tissue and correlated with tumor size and stage. Our findings offer new insights into the pathogenesis of CSCC and suggest that B7-H4 and B7-H5 are novel tissue biomarkers and promising therapeutic targets for CSCC.

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“…Strikingly, B7-H4 expression in tumors has minimal overlap with PD-L1 (also known as B7-H1) expression ( 17–19 ), which may reflect functional redundancy in inhibiting antitumor immunity. Consequently, in B7-H4+ tumors where PD-L1 expression is absent or low and PD-(L)1 immune checkpoint inhibitors may not be effective, a B7-H4 targeted agent may be an effective treatment option.…”

Section: Introductionmentioning

confidence: 99%

Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody–Drug Conjugate for the Treatment of Cancer

Toader

Fessler²,

Collins

et al. 2023

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADCs) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody (drug-to-antibody ratio, DAR). To allow for ADC optimization for a given target antigen, we developed Dolasynthen, a novel ADC platform based on the payload auristatin hydroxypropylamide (AF-HPA), that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific Dolasynthen DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer patient-derived xenografts (PDX), XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a Phase 1 study (NCT05377996) in cancer patients.

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The B7H4-PDL1 classifier stratifies immuno-phenotype in cervical cancer

Cited by 5 publications

References 44 publications

KDM6B enhances anti-PD-L1 immunotherapy efficacy by increasing CD8+ T-cell infiltration in colorectal cancer

KDM6B enhances anti-PD-L1 immunotherapy efficacy by increasing CD8+ T-cell infiltration in colorectal cancer

Aberrant expression of B7-H4 and B7-H5 contributes to the development of cutaneous squamous cell carcinoma

Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody–Drug Conjugate for the Treatment of Cancer

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