Dataset Information

The application of HER2 and CD47 CAR-macrophage in ovarian cancer.

ABSTRACT:

Background

The chimeric antigen receptor (CAR)-T therapy has a limited therapeutic effect on solid tumors owing to the limited CAR-T cell infiltration into solid tumors and the inactivation of CAR-T cells by the immunosuppressive tumor microenvironment. Macrophage is an important component of the innate and adaptive immunity, and its unique phagocytic function has been explored to construct CAR macrophages (CAR-Ms) against solid tumors. This study aimed to investigate the therapeutic application of CAR-Ms in ovarian cancer.

Methods

In this study, we constructed novel CAR structures, which consisted of humanized anti-HER2 or CD47 scFv, CD8 hinge region and transmembrane domains, as well as the 4-1BB and CD3ζ intracellular domains. We examined the phagocytosis of HER2 CAR-M and CD47 CAR-M on ovarian cancer cells and the promotion of adaptive immunity. Two syngeneic tumor models were used to estimate the in vivo antitumor activity of HER2 CAR-M and CD47 CAR-M.

Results

We constructed CAR-Ms targeting HER2 and CD47 and verified their phagocytic ability to ovarian cancer cells in vivo and in vitro. The constructed CAR-Ms showed antigen-specific phagocytosis of ovarian cancer cells in vitro and could activate CD8⁺ cytotoxic T lymphocyte (CTL) to secrete various anti-tumor factors. For the in vivo model, mice with human-like immune systems were used. We found that CAR-Ms enhanced CD8⁺ T cell activation, affected tumor-associated macrophage (TAM) phenotype, and led to tumor regression.

Conclusions

We demonstrated the inhibition effect of our constructed novel HER2 CAR-M and CD47 CAR-M on target antigen-positive ovarian cancer in vitro and in vivo, and preliminarily verified that this inhibitory effect is due to phagocytosis, promotion of adaptive immunity and effect on tumor microenvironment.

SUBMITTER: Chen Y

PROVIDER: S-EPMC10517545 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

The application of HER2 and CD47 CAR-macrophage in ovarian cancer.

Chen Yizhao Y Zhu Xiangling X Liu Hanze H Wang Cunzhi C Chen Yu Y Wang Huihui H Fang Yilong Y Wu Xuming X Xu Yuting Y Li Chunhua C Lv Xinyue X Huang Jinghua J Han Xintong X Li Ruilin R Hong Wenming W Yu Zhiying Z Wei Wei W Tu Jiajie J

Journal of translational medicine 20230922 1

<h4>Background</h4>The chimeric antigen receptor (CAR)-T therapy has a limited therapeutic effect on solid tumors owing to the limited CAR-T cell infiltration into solid tumors and the inactivation of CAR-T cells by the immunosuppressive tumor microenvironment. Macrophage is an important component of the innate and adaptive immunity, and its unique phagocytic function has been explored to construct CAR macrophages (CAR-Ms) against solid tumors. This study aimed to investigate the therapeutic app ...[more]

PMID: 37740183

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Project description:BackgroundEpithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy with limited treatment options. CD47 is a critical immune checkpoint for tumor immune evasion and has been targeted in various clinical trials. This study aimed to assess the impact of chemotherapy on CD47 expression in EOC in order to determine the potential and optimal timing of CD47-targeted therapy in ovarian cancer. We analyzed the expression of CD47 in ovarian cancer and the effect of chemotherapy on the expression of CD47 in ovarian cancer tissues. Furthermore, we investigated the effect of chemotherapy on the expression of CD47 in ovarian cancer cells.MethodsCD47 expression was examined using immunohistochemistry (IHC) of specimens from 78 patients with EOC who underwent neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) with paired tissue specimens obtained before and after NACT. A retrospective review of the medical records was conducted to correlate demographic and survival data. Subsequently, we employed reverse transcription quantitative polymerase chain reaction (RT-qPCR) and flow cytometry analysis to examine and compare CD47 expression across human ovarian surface epithelial cell line (HOSE), SKOV3, and ES2 cells and to characterize the changes in CD47 expression in SKOV3 and ES2 cells after cisplatin treatment.ResultsCD47 expression was observed in 63 out of 78 (80.8%) cases before NACT. The expression of CD47 was not associated with the clinicopathological characteristics or the prognosis of patients with EOC. After three cancer specimens were excluded due to the absence of cancer cells following NACT, Wilcoxon exact tests of 75 pairs of matched specimens indicated that the expression of CD47 increased after chemotherapy (P=0.006). CD47 was expressed at varying levels in HOSE ovarian epithelial cells and SKOV3 and ES2 ovarian cancer cells. Notably, the CD47 messenger RNA (mRNA) expression of HOSE cells was observed to be lower than that of the SKOV3 and ES2 ovarian cancer cells (P<0.001). Following treatment with cisplatin, RT-qPCR indicated an increase in CD47 mRNA expression in SKOV3 and ES2 cells (P<0.001). Flow cytometry revealed a notable elevation in the cell surface CD47 protein mean fluorescence intensity of cisplatin-treated SKOV3 and ES2 cells (P<0.001).ConclusionsCD47 is highly expressed in ovarian cancer, and NACT increases the expression of CD47, which may contribute to tumor immune evasion. It is possible that platinum-based chemotherapy may result in elevated CD47 mRNA expression and cell surface CD47 protein expression.

Project description:Human epidermal growth factor receptor 2 (HER2) is a highly expressed tumor marker in epithelial ovarian cancer, and its overexpression is considered to be a potential factor of poor prognosis. Therefore, monitoring the expression of HER2 receptor in tumor tissue provides favorable conditions for accurate localization, diagnosis, targeted therapy, and prognosis evaluation of cancer foci. Affibody has the advantages of high affinity, small molecular weight, and stable biochemical properties. The molecular probes of radionuclide-labeled HER2 affibody have recently shown broad application prospects in the diagnosis and treatment of ovarian cancer; the aim is to introduce radionuclides into the cancer foci, display systemic lesions, and kill tumor cells through the radioactivity of the radionuclides. This process seamlessly integrates the diagnosis and treatment of ovarian cancer. Current research and development of new molecular probes of radionuclide-labeled HER2 affibody should focus on overcoming the deficiencies of non-specific uptake in the kidney, bone marrow, liver, and gastrointestinal tract, and on reducing the background of the image to improve image quality. By modifying the amino acid sequence; changing the hydrophilicity, surface charge, and lipid solubility of the affibody molecule; and using different radionuclides, chelating agents, and labeling conditions to optimize the labeling method of molecular probes, the specific uptake of molecular probes at tumor sites will be improved, while reducing radioactive retention in non-target organs and obtaining the best target/non-target value. These measures will enable the clinical use of radionuclide-labeled HER2 affibody molecular probes as soon as possible, providing a new clinical path for tumor-specific diagnosis, targeted therapy, and efficacy evaluation. The purpose of this review is to describe the application of radionuclide-labeled HER2 affibody in the imaging and treatment of ovarian cancer, including its potential clinical value and dilemmas.

Dataset Information

The application of HER2 and CD47 CAR-macrophage in ovarian cancer.

Background

Methods

Results

Conclusions

Publications

The application of HER2 and CD47 CAR-macrophage in ovarian cancer.

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