CD38 Drives Ovarian Cancer Growth and Reshapes Its Immune Microenvironment
New research shows CD38 fuels epithelial ovarian cancer progression via PI3K-AKT and IL-6 pathways, while a CD38 inhibitor curbs tumor growth and immune suppression.
Summary
Researchers found that CD38, a transmembrane glycoprotein enzyme, is significantly overexpressed in epithelial ovarian cancer (EOC) tumor cells, immune cells, and cancer-associated fibroblasts. Using cell line experiments, mouse models, and large public datasets, the team demonstrated that CD38 promotes cancer cell proliferation, migration, and metastasis through the PI3K-AKT-mTOR and IL-6-JAK-STAT3 signaling pathways. CD38 also remodels the tumor microenvironment by facilitating immune and stromal cell infiltration, impairing T cell tumor recognition, and enhancing cancer-associated fibroblast crosstalk with tumor cells. Critically, treating mice with a CD38-specific inhibitor (Compound 78c) reduced tumor growth, immune infiltration, and PD-L1 expression, suggesting CD38 as a promising immunotherapy target in ovarian cancer.
Detailed Summary
Epithelial ovarian cancer (EOC) carries the highest mortality among gynecological malignancies, with a five-year survival rate around 45% due to frequent chemotherapy resistance and limited benefit from existing immune checkpoint blockade therapies. Identifying new therapeutic targets that simultaneously address tumor cell behavior and the immunosuppressive tumor microenvironment (TME) is urgently needed.
This study systematically examined CD38—a multifunctional NAD+-metabolizing transmembrane glycoprotein previously validated as a therapeutic target in multiple myeloma—in the context of EOC. The researchers integrated analyses from TCGA, GTEx, CCLE, GEPIA2021, TISCH2, and TISIDB databases with tissue microarray immunohistochemistry (IHC) on 99 primary ovarian cancer and 18 normal ovary specimens. CD38 was significantly upregulated in EOC tumor cells compared to normal ovarian tissue, with higher expression correlating with advanced stage and poor prognosis.
Functional experiments using lentiviral overexpression and knockdown in SKOV3, A2780, CAOV3, and ID8 cell lines revealed that CD38 promotes cell proliferation, colony formation, migration, and invasion in vitro. In vivo, CD38-overexpressing SKOV3 cells showed enhanced peritoneal metastasis in nude mice, and CD38-overexpressing ID8 cells formed larger subcutaneous tumors in immunocompetent C57BL/6 mice. Mechanistically, CD38 activated the PI3K-AKT-mTOR and IL-6-JAK-STAT3 signaling pathways, confirmed by western blot and RT-qPCR. GSEA analyses further enriched these pathways in high-CD38 tumors.
Beyond tumor cells, CD38 was overexpressed in tumor-infiltrating lymphocytes (TILs) and fibroblast-like cells in IHC-stained TMA sections. CIBERSORT immune infiltration analysis of TCGA-OV data showed that high CD38 expression correlated with increased infiltration of immunosuppressive cell types. WGCNA and TIP database analyses revealed that CD38 negatively correlated with steps of the cancer-immunity cycle including T cell priming and tumor cell recognition. Additionally, CD38 expression correlated positively with multiple immune checkpoint molecules including PD-L1, CTLA-4, LAG-3, and TIM-3, and TIDE algorithm analysis predicted poorer response to immune checkpoint blockade in high-CD38 tumors. Single-cell RNA sequencing data confirmed that cancer-associated fibroblasts (CAFs) in the EOC TME are a major CD38-expressing population, with high CD38 in the stromal compartment enhancing IL-6-driven signaling between iCAFs and tumor cells.
The therapeutic potential of CD38 inhibition was tested using Compound 78c, a selective CD38 inhibitor, administered intraperitoneally in the ID8 syngeneic mouse model. Treatment significantly reduced tumor volume and weight compared to controls. Flow cytometry revealed decreased infiltration of CD4+ and CD8+ T cells in tumors and reduced CD38 surface expression on T cells, alongside decreased PD-L1 expression—suggesting the inhibitor can simultaneously suppress tumor growth and remodel the immunosuppressive TME. These findings position CD38 as a compelling dual-target in EOC: acting both as a direct tumor driver and as an immunosuppressive TME architect.
Key Findings
- CD38 is significantly overexpressed in EOC tumor cells, TILs, and fibroblasts, correlating with advanced disease stage.
- CD38 drives EOC proliferation and metastasis via PI3K-AKT-mTOR and IL-6-JAK-STAT3 pathway activation.
- High CD38 expression reshapes the TME by increasing immunosuppressive cell infiltration and impairing T cell tumor recognition.
- CD38 positively correlates with PD-L1, CTLA-4, LAG-3, and TIM-3, predicting poor ICB response.
- CD38 inhibitor Compound 78c reduced tumor growth, immune infiltration, and PD-L1 expression in a mouse EOC model.
Methodology
The study combined IHC on a 99-patient ovarian cancer TMA, lentiviral gene manipulation in multiple cell lines, syngeneic and xenograft mouse models, and multi-database bioinformatics (TCGA, scRNA-seq via TISCH2, CIBERSORT, GSEA, WGCNA, TIDE). CD38 inhibitor Compound 78c was evaluated in vivo with flow cytometry immune profiling of dissociated tumor tissue.
Study Limitations
The in vivo inhibitor study used only one mouse model (syngeneic ID8) and a single dose regimen, limiting translational confidence. The clinical TMA cohort of 99 patients lacked survival outcome data linked to CD38 IHC subgroups. Mechanistic dissection of CAF-specific CD38 contributions versus tumor-cell-intrinsic CD38 effects was not fully separated experimentally.
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