The CD40‐CD154 interaction would correlate with proliferation and immune escape in pancreatic ductal adenocarcinoma

Shoji, Yasushi; Miyamoto, Masaki; Ishikawa, Kenji; Yoshioka, Takayuki; Mishra, Roshan; Ichinokawa, Kazuomi; Matsumura, Yuko; Itoh, Tomoo; Shinohara, Toshiya; Hirano, Satoshi; Kondo, Satoshi

doi:10.1002/jso.21812

Cited by 9 publications

(8 citation statements)

References 39 publications

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“…The functional relevance of the CD40/CD40L interac tions in malignant tumors is variable and likely context dependent. It has been shown that CD40/CD40L interac tions or up-regulation of CD40 correlated with poor prognosis in pancreatic ductal carcinoma [14] and non-small lung cancer [15], whereas CD40 ligation exerts antiproliferative effects and apoptosis induction in malignant ovarian tumors [16] and melanoma cell lines [17]. Previous studies also showed that not only TNFα but also the CD40/CD40L interactions exert a direct cytotoxicity of HeLa CD40 cells in the presence of a protein inhibitor [9].…”

Section: Discussionmentioning

confidence: 99%

CD40/CD40 LIGAND INTERACTIONS AND TNFα TREATMENT REDUCE ACTIVITY OF P105 PROMOTER OF THE HUMAN PAPILLOMA VIRUS-18 IN VITRO

Altenburg¹,

Abdel-Naser²,

Nikolakis³

et al. 2016

Exp. Onc.

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Background: Cervical carcinoma cells including those infected with the oncogenic human papilloma virus (HPV) and several cervical carcinoma cell lines show a strong expression of the CD40 receptor, unlike benign cervical epithelial cells infected with HPV. The functional relevance of this up-regulated expression in the tumor is not fully understood. Nevertheless, it might offer a unique possibility to target those malignant cells due to the antiviral and antitumoral effects of the CD40/CD40 ligand (CD40L) interactions. Aim: In vitro assessment of the effect of CD40L on HPV 18-P105 promoter activity and the subsequent release of IL-6 by the promoter transfected HeLaCD40 cells, which express CD40 constitutively. Material and Methods: Transfection of HeLaCD40 cells was achieved by electroporation after optimizing the parameters by the pCMV-β-Gal vector and β-Gal stain. Transfected HeLaCD40 cells were challenged with BHKCD40L and TNFα, in addition to BHKwt and medium alone as controls. HPV18P105 promoter activity was demonstrated by luciferase reporter gene assay while IL-6 was assessed by ELISA. Results: CD40/ CD40L interactions and TNFα treatment significantly reduced HPV18-P105 promoter activity (56.0 ± 10.2% and 64.1 ± 9.1% vs. control, respectively; p < 0.001). Likewise, IL-6, which is a sensitive cytokine of CD40 activation, was significantly increased in HeLaCD40 cells in the same experiments (2.7 fold after stimulation with BHKCD40L and 5.2 fold after stimulation with TNFα vs. control; p < 0.01 and p < 0.001, respectively). Conclusion: It is likely that the CD40/CD40L interactions and TNFα are effective against cervical carcinomas by repressing transcriptional activity of HPV promoter. This can result in new adjuvant treatments.

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Section: Discussionmentioning

confidence: 99%

CD40/CD40 LIGAND INTERACTIONS AND TNFα TREATMENT REDUCE ACTIVITY OF P105 PROMOTER OF THE HUMAN PAPILLOMA VIRUS-18 IN VITRO

Altenburg¹,

Abdel-Naser²,

Nikolakis³

et al. 2016

Exp. Onc.

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“…235 The normal expression and interaction of CD40 and CD154 by immune cells result in the proliferation of the immune response with the potential to ultimately affect antitumor immunity. In a recent study by Shoji et al, 236 it was found that both CD40 and CD154 are expressed by PDAC cell lines and patient specimens, and although the study did not directly evaluate TILs, they found the frequency of CD154 expression on TILs to be low in their xenograft model. These findings suggest that PDAC cells can potentially use CD40 and CD154 expression as an autocrine mechanism to promote tumor cell proliferation as well as potentially alter CD154 expression on TILs.…”

Section: Immune Failure and Tumor Escape In Pdacmentioning

confidence: 97%

“…A good example of this was the finding that very high expression of CD154 in patient specimens correlated with a favorable prognosis. 236 On the one hand, PDAC cells promote their own growth with the expression of CD40-CD154 and immune cell suppression with secretion of IL-10. The ligation of CD40 on these tumor cells leads to the secretion of proinflammatory cytokines IL-6 and IL-12 that could ultimately result in an antitumor response.…”

Section: Immune Failure and Tumor Escape In Pdacmentioning

confidence: 99%

Pancreatic Ductal Adenocarcinoma: A Review of Immunologic Aspects

Wachsmann

Pop

Vitetta

2012

Journal of Investigative Medicine

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With the continued failures of both early diagnosis and treatment options for pancreatic cancer, it is now time to comprehensively evaluate the role of the immune system on the development and progression of pancreatic cancer. It is important to develop strategies that harness the molecules and cells of the immune system to treat pancreatic cancer. This review will focus primarily on the role of immune cells in the development and progression of pancreatic ductal adenocarcinoma (PDAC). We will evaluate what is known about the interaction of immune cells with the tumor microenvironment and their role in tumor growth and metastasis. We will conclude with a brief discussion of therapy for pancreatic cancer and the potential role for immunotherapy. We hypothesize that the role of the immune system in tumor development and progression is tissue specific. Our hope is that better understanding of this process will lead to better treatments for this devastating disease.

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“…CD40 on the surface of APCs could bind with the CD40 ligand expressed on activated CD4+ T cells, thus forming a stimulatory loop. CD40 and its ligand (CD154) are both expressed in a subset of pancreatic patients, and the high expression of CD40 ligand is associated with significantly better prognosis than others [102]. The activation of CD40 with a CD40 agonist in combination with gemcitabine is indicated to promote accumulation of tumoricidal macrophages within the tumors in the KPC mouse model, which resulted in stromal collapse and tumor regression in the KPC mouse model and some advanced-stage pancreatic cancer patients [103,104].…”

Section: Immunotherapy and Other State-of-the-art Molecular Optionsmentioning

confidence: 99%

Current Clinical Strategies of Pancreatic Cancer Treatment and Open Molecular Questions

Brunner

Krautz

et al. 2019

IJMS

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Pancreatic cancer is one of the most lethal malignancies and is associated with a poor prognosis. Surgery is considered the only potential curative treatment for pancreatic cancer, followed by adjuvant chemotherapy, but surgery is reserved for the minority of patients with non-metastatic resectable tumors. In the future, neoadjuvant treatment strategies based on molecular testing of tumor biopsies may increase the amount of patients becoming eligible for surgery. In the context of non-metastatic disease, patients with resectable or borderline resectable pancreatic carcinoma might benefit from neoadjuvant chemo- or chemoradiotherapy followed by surgeryPatients with locally advanced or (oligo-/poly-)metastatic tumors presenting significant response to (neoadjuvant) chemotherapy should undergo surgery if R0 resection seems to be achievable. New immunotherapeutic strategies to induce potent immune response to the tumors and investigation in molecular mechanisms driving tumorigenesis of pancreatic cancer may provide novel therapeutic opportunities in patients with pancreatic carcinoma and help patient selection for optimal treatment.

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The CD40‐CD154 interaction would correlate with proliferation and immune escape in pancreatic ductal adenocarcinoma

Abstract: These results suggest that the CD40-CD154 interaction would correlate with cell proliferation and secretion of cytokines in PDAC cells, and CD154 overexpression could be a favorable prognostic factor in PDAC patients.

Cited by 9 publications

References 39 publications

CD40/CD40 LIGAND INTERACTIONS AND TNFα TREATMENT REDUCE ACTIVITY OF P105 PROMOTER OF THE HUMAN PAPILLOMA VIRUS-18 IN VITRO

CD40/CD40 LIGAND INTERACTIONS AND TNFα TREATMENT REDUCE ACTIVITY OF P105 PROMOTER OF THE HUMAN PAPILLOMA VIRUS-18 IN VITRO

Pancreatic Ductal Adenocarcinoma: A Review of Immunologic Aspects

Current Clinical Strategies of Pancreatic Cancer Treatment and Open Molecular Questions

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