Direct Interaction of CD40 on Tumor Cells with CD40L on T Cells Increases the Proliferation of Tumor Cells by Enhancing TGF-β Production and Th17 Differentiation

Abstract

It has recently been reported that the CD40-CD40 ligand (CD40L) interaction is important in Th17 development. In addition, transforming growth factor—beta (TGF-β) promotes tumorigenesis as an immunosuppressive cytokine and is crucial in the development of Th17 cells. This study investigated the role of CD40 in breast cancer cells and its role in immunosuppressive function and tumor progression. CD40 was highly expressed in the breast cancer cell line MDA-MB231, and its stimulation with CD40 antibodies caused the up-regulation of TGF-β. Direct CD40-CD40L interaction between MDA-MB231 cells and activated T cells also increased TGF-β production and induced the production of IL-17, which accelerated the proliferation of MDA-MB231 cells through the activation of STAT3. Taken together, the direct CD40-CD40L interaction of breast tumor cells and activated T cells increases TGF-β production and the differentiation of Th17 cells, which promotes the proliferation of breast cancer cells.

CD40 Expression in Human Esophageal Squamous Cell Carcinoma Is Associated with Tumor Progression and Lymph Node Metastasis

“…In addition to exerting a direct anti-proliferative effect on tumor cells, previous studies have demonstrated a role for CD40 in immunosuppression within the tumor micro- and CD154 on activated T-cells increased TGFβ production and the differentiation of Th17 cells, resulting in acceleration of cancer cell proliferation (35). These findings strongly indicate that CD40 expression might work in favor of cancer progression and immuno-evasion mechanisms in the cancer microenvironment.…”

“…In the present study, a significant increase in IL6 production was induced by rhCD154 in ESCC cell lines, even in the cell line with low CD40 expression. Previous studies have demonstrated that CD40 induces the up-regulation of IL6 production in various tumors including multiple myeloma (36), breast cancer (35), ovarian carcinoma (33), and non-small cell lung cancer (37). Furthermore, IL6 has been reported to induce tumor progression in various human malignancies, including esophageal cancer (38).…”

Transcriptional splice variants of CD40 and its prognostic value in breast cancer

“…Interestingly, the ER + /PR + /HER2 + breast cancer cell line BT-474 does express Variant 3 in the presence of LPS. High CD40 expression was detected in the cytoplasm of hormonereceptor-positive breast cancer, whereas it was detected on the surface membrane of triple-negative breast cancer (Kim et al, 2015;Slobodova et al, 2011). We thought that the basal expression of V3, which has low ligand binding capacity, might be quite low in BT-474 and could be stimulated by LPS.…”

Association of Single Nucleotide Polymorphisms in the Apoptosis-Related Genes <i>TP63</i> and <i>CD40 </i>with Risk for Lung Cancer in a Chinese Han Population

“…Individuals who harbored both the CC genotype of rs1535045 and the GG genotype of rs6790167 had higher risk for lung adenocarcinoma. The binding of CD40 to its receptors activates transcription factor NF-κB and increases the synthesis of anti-apoptotic proteins, as well as activates TGF-β signaling pathways (Kim et al 2015). Since TP63 is downstream target of NF-κB (Wu et al 2010), the expression of an isoform of TP63 (ΔNp63) is increased when CD40 activated NF-κB (Fukunishi et al 2010).…”