Targeting immunotherapy for bladder cancer using anti‐<scp>CD</scp>3× B7‐H3 bispecific antibody

Ma, Wenxin; Ma, Juan; Ma, Ping; Lei, Ting; Zhao, Man; Zhang, Man

doi:10.1002/cam4.1775

Cited by 17 publications

(11 citation statements)

References 32 publications

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“…However, the high level of B7-H3 expression was observed in a wide range of carcinomas, including the bladder cancer, brain cancer and prostate cancer. [5][6][7] Previous reports indicated that the overexpression of B7-H3 contributes to tumor immune evasion and promotes tumor metastatic, resulting in a poor prognosis. 8 Also, Qing Ge and his colleagues have reported that B7-H3 could promote multiple myeloma cell survival and proliferation through a ROS-dependent signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

<p>B7-H3 Induces Ovarian Cancer Drugs Resistance Through An PI3K/AKT/BCL-2 Signaling Pathway</p>

Zhou¹,

Zhao²

2019

CMAR

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Purpose: This study was aimed to investigate the underlying mechanism of B7-H3 induced ovarian cancer proliferation and drugs resistance. Materials and methods: We compared the expression of B7-H3 in ovarian tumor tissues from high-malignant or low-malignant patients by immunohistochemistry. We established B7-H3 overexpression and knockout ovarian cells by CRISPR-Cas9 technology and examined the expression of the PI3K/AKT/BCL-2 signals in tumor cells by Western blot or immunofluorescence. We detected the B7-H3 overexpression ovarian cancer cells drugs resistance by CCK8 cell proliferation analysis and Annexin V/PI staining. Tumor-bearing mice were used to investigate the anticancer effects of PI3K/AKT inhibitors in combination with B7-H3 neutralizing antibodies. Results: Enhanced expression of B7-H3 was observed in ovarian tumor tissues from highmalignant patients compared to those from low-malignant patients. Notably, B7-H3 overexpression caused enhanced cells proliferation and chemo-resistance in vitro and in vivo through the activation of PI3K/AKT signaling pathways and up-regulation of BCL-2 protein.Combination of chemotherapeutic agents and B7-H3 neutralizing antibodies efficiently reverses the drugs resistance induced by B7-H3, resulting in improved anticancer effects in ovarian cancer. Conclusion: B7-H3 expression induces the activation the PI3K/AKT signaling pathway and up-regulates BCL-2 in protein level, resulting in the sustained growth and chemo-resistance in ovarian cancer. Blockade of B7-H3 signals efficiently reverses the chemo-resistance, which provides an innovative target in ovarian cancer treatment.

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Section: Introductionmentioning

confidence: 99%

<p>B7-H3 Induces Ovarian Cancer Drugs Resistance Through An PI3K/AKT/BCL-2 Signaling Pathway</p>

Zhou¹,

Zhao²

2019

CMAR

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“…Elevated expression of CD276 in bladder cancer samples was reported previously [ 22 ] and success of experimental anti-CD276 antibody therapies raised hope for a new immune checkpoint therapy [ 6 , 15 , 16 ]. Our in vitro data using the well-established bladder cancer cell lines HT1197, TCCsup, RT4, and 5637 in comparison to four urothelial cell populations generated from explants from healthy ureters corroborated a significant overexpression of CD276 in BC cell lines.…”

Section: Discussionmentioning

confidence: 90%

“…In another study, CD276 prevented activation of anti-tumor responses by blocking CD4 + Th 1 - activation [ 14 ]. There is experimental evidence promising success of anti-CD276 tumor therapies [ 6 , 14 – 16 ], and several clinical studies are underway or already completed (see https://clinicaltrials.gov ).…”

Section: Introductionmentioning

confidence: 99%

Expression patterns of the immune checkpoint ligand CD276 in urothelial carcinoma

et al. 2021

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Background CD276 is an immune checkpoint molecule. Elevated CD276 expression by urothelial carcinoma is associated with poor prognosis, but little is known about its expression across different tumor stages. We therefore investigated CD276 expression in bladder cancer (BC) cells and in tissue samples of BC stages from pT2 to pT4. Methods CD276 expression was explored in 4 urothelial cancer cell lines and 4 primary normal urothelial cell populations by quantitative RT-PCR, Western blot and flow cytometry. CD276 was investigated in bladder tumors from 98 patients by immunohistochemistry using a score (0–300) incorporating both, staining intensity and area of CD276 staining. Normal appearing urothelium in the bladder of the same patients served as controls. Results The urothelial carcinoma cell lines expressed significantly higher levels of CD276 on transcript (p < 0.006), total protein levels (p < 0.005), and on the cell surface (p < 0.02) when compared to normal urothelial cells. In pT2–T4 tumor tissue samples, CD276 was overexpressed (median score 185) when compared to corresponding healthy tissues from the same patients (median score 50; p < 0.001). No significant differences in CD276 expression were recorded in late, locally advanced ≥ pT3a tumors (median score 185) versus organ-confined < pT3a tumors (median score 190), but it was significantly lower in the normal urothelial tissue associated with ≥ pT3a tumors (median score 40) versus < pT3a tumors (median score 80; p < 0.05). Conclusion CD276 expression is significantly elevated in urothelial carcinoma cells in all stages but varies between individuals considerably. Reduced CD276 expression in normal urothelial cells may imply that these cells would be protected from CD276-mediated immuno therapies.

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“…Higher CD3 infiltration exhibited improved survival of BLCA, while the correlations of CD3E and BLCA have not been investigated. However, targeting immunotherapy for BLCA using anti-CD3×B7-H3, anti-CD3×CD155, and anti-CD3xEGFR or anti-CD3xHER2 bispecific antibody may provide novel strategies for BLCA therapy ( 40 – 42 ).…”

Section: Discussionmentioning

confidence: 99%

CXCL12 and CD3E as Indicators for Tumor Microenvironment Modulation in Bladder Cancer and Their Correlations With Immune Infiltration and Molecular Subtypes

Liu

Zhang

et al. 2021

Front. Oncol.

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Bladder cancer (BLCA) represents the ninth most common malignant tumor in the world and is characterized by high recurrence risk. Tumor microenvironment (TME) plays an important role in regulating the progression of BLCA. Immunotherapy, including Bacillus Calmette-Guerin (BCG) and programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1), is closely associated with TME and is widely used for treating BLCA. But parts of BLCA patients have no response to these treatment ways, thus a better understanding of the complex TME of BLCA is still needed. We downloaded the gene expression profile and corresponding clinical information of 414 BLCA patients from the TCGA database. Via the ESTIMATE and CIBERSORT algorithm, we identified the two hub genes (CXCL12 and CD3E) and explored their correlations with immune infiltration. We found that BLCA patients with higher expression of CXCL12 and lower expression of CD3E had prolonged survival. Gene set enrichment analysis (GSEA) revealed that both CXCL12 and CD3E were enriched in immune-related pathways. We also discovered that stromal score and the level of CXCL12 were higher in luminal subtype, and immune score and the level of CD3E were higher in the basal subtype. Furtherly, we found that CXCL12 was associated with naive B cells, resting mast cell, M2 macrophages, follicular helper T cells, and dendritic cells. CD8+ T cells, CD4+ T cells, regulatory T cells (Tregs), and macrophages were correlated with CD3E. In conclusions, we found that CXCL12 and CD3E might serve as indicators of TME modulation in BLCA. Therapy targeting CXCL12 and CD3E had the potential as novel therapeutic strategy.

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Targeting immunotherapy for bladder cancer using anti‐CD3× B7‐H3 bispecific antibody

Cited by 17 publications

References 32 publications

<p>B7-H3 Induces Ovarian Cancer Drugs Resistance Through An PI3K/AKT/BCL-2 Signaling Pathway</p>

<p>B7-H3 Induces Ovarian Cancer Drugs Resistance Through An PI3K/AKT/BCL-2 Signaling Pathway</p>

Expression patterns of the immune checkpoint ligand CD276 in urothelial carcinoma

CXCL12 and CD3E as Indicators for Tumor Microenvironment Modulation in Bladder Cancer and Their Correlations With Immune Infiltration and Molecular Subtypes

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