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CD40L membrane retention enhances the immunostimulatory effects of CD40 ligation
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Elmetwali, Taha, Salman, Asmaa, Wei, Wenbin, Hussain, Syed A., Young, Lawrence S. and Palmer, Daniel H. (2020) CD40L membrane retention enhances the immunostimulatory effects of CD40 ligation. Scientific Reports, 10 (1). 342. doi:10.1038/s41598-019-57293-y ISSN 2045-2322.
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WRAP-CD40L-membrance-retention-immunostimulatory-ligation-Young-2020.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (2404Kb) | Preview |
Official URL: http://dx.doi.org/10.1038/s41598-019-57293-y
Abstract
In carcinomas, the nature of CD40 ligand shapes the outcome of CD40 ligation. To date, the consequences of membrane-bound CD40L (mCD40L) on its immune-stimulatory function are unknown. Here, we examined the impact of mCD40L versus soluble CD40L (sCD40L) on T24 bladder carcinoma gene expression profiling. Of 410 differentially expressed genes, 286 were upregulated and 124 downregulated by mCD40L versus sCD40L. Gene ontology enrichment analysis revealed immune-stimulatory function as the most significant enriched biological process affected by upregulated transcripts, while those downregulated were critical for cell growth and division. Furthermore, immature dendritic cells (iDC) responded to mCD40L with enhanced maturation and activation over sCD40L evidenced by higher expression levels of CD83, CD86, HLA-DR and CD54, increased secretion of IL12 and IL10 and higher tumour-antigen (TA) uptake capacity. Furthermore, autologus CD3+ T cells responded to TA-loaded mCD40L-activated DC with increased proliferation and cytotoxic response (CD107a and IFN-γ-producing CD3+ CD8+ T cells) to the tumour-loaded autologous PBMCs compared to sCD40L. Thus, these data indicate that mCD40L enhances the immunostimulatory capacity over sCD40L. Furthermore, the ability of mCD40L to also directly induce cell death in CD40-expressing carcinomas, subsequently releasing tumour-specific antigens into the tumour microenvironment highlights the potential for mCD40L as a multi-faceted anti-cancer immunotherapeutic.
| Item Type: | Journal Article | |||||||||
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| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) | |||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Cancer, Antineoplastic agents -- Research, Cancer -- Gene therapy, Immunological adjuvants | |||||||||
| Journal or Publication Title: | Scientific Reports | |||||||||
| Publisher: | Nature Publishing Group | |||||||||
| ISSN: | 2045-2322 | |||||||||
| Official Date: | 15 January 2020 | |||||||||
| Dates: |
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| Volume: | 10 | |||||||||
| Number: | 1 | |||||||||
| Article Number: | 342 | |||||||||
| DOI: | 10.1038/s41598-019-57293-y | |||||||||
| Status: | Peer Reviewed | |||||||||
| Publication Status: | Published | |||||||||
| Access rights to Published version: | Open Access (Creative Commons) | |||||||||
| Date of first compliant deposit: | 21 January 2020 | |||||||||
| Date of first compliant Open Access: | 30 January 2020 | |||||||||
| RIOXX Funder/Project Grant: |
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