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1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells

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johan
(@j)
Joined: 4 years ago
Posts: 1190
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Abstract

Background Epidemiological surveys have revealed that low serum vitamin D level was correlated with increased risk of tumors. Dysfunctional T cells in patients with tumor are characterized as exhausted with high levels of immune checkpoint receptors (ICRs). However, whether the reduced level of vitamin D in patients with cancer correlates with cytotoxic T-cell exhaustion is unknown.

Methods Periphery blood samples from 172 patients with non-small cell lung cancer (NSCLC) were prospectively collected. Patients with NSCLC received one course of intravenous docetaxel (75 mg/m2) followed by treatment with or without rocaltrol at a dose of 0.5–2.0 µg/day for total of 3 weeks. We performed phenotypical and functional analysis of T-cell through flow cytometry. Vitamin D receptor (VDR) knockout and overexpression CD8+ and Vδ2+ T cells were constructed using Cas9-gRNA targeted and overexpressing approaches to identify 1α,25(OH)2D3/VDR-mediated transcription regulation for ICRs or antitumor activity in T cells.

Results We show that serum level of vitamin D is negatively correlated with expression of programmed cell death-1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), but positively correlated with CD28 expression on CD8+ and Vγ9Vδ2+ T cells in patients with NSCLC. 1α,25(OH)2D3, the active form of vitamin D, promotes the nuclear translocation of VDR, which binds to the promoter region of Pdcd1, Tim3, and Tigit genes and inhibits their expression. Besides, 1α,25(OH)2D3 pretreatment also promotes the methylation of CpG island in the promoter region of the Pdcd1 gene and increases H3K27 acetylation at the promoter region of the Cd28 gene, which leads to surface PD-1 downregulation and CD28 upregulation, respectively. We further reveal that VDR-mediated Ca2+ influx enhanced expression of Th1 cytokines via T-cell receptor activation. Functionally, 1α,25(OH)2D3 pretreated CD8+ T cells or Vγ9Vδ2+ T cells showed increased Th1 cytokine production and enhanced antitumor immunity. Finally, oral 1α,25(OH)2D3 could also decrease expression of PD-1, Tim-3, TIGIT and increase expression of CD28, resulting in cytokine production (associated with antitumor immunity) by cytotoxic T cells of patients with NSCLC.

Conclusions Our findings uncover the pleiotropic effects of 1α,25(OH)2D3 in rescuing the exhausted phenotype of human cytotoxic T cells in patients with tumor and in promoting their antitumor immunity.


   
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medline
(@aliml2)
Joined: 8 months ago
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1alpha,25(OH)2D3 (calcitriol) is a vitamin D receptor (VDR) agonist, so other VDR activators such as curcumin, gamma-tocotrienol, etc. may also enhance antitumor immunity.

https://doi.org/10.1111/j.1753-4887.2008.00093.x

In blood tests, biologically inactive vitamin D (25-D) is usually measured, while the level of the active form of vitamin D (1,25-D) is more important.

It is interesting, in autoimmune diseases the level of 1,25-D is higher than 25-D, I guess in cancer the 1,25-D/25-D ratio is lower.

https://doi.org/10.1111/j.1749-6632.2009.04875.x

In addition, the level of Th1 cytokines is increased in autoimmune diseases, but in cancer, as in allergic diseases, Th2 cytokines are elevated.  

In normal circumstances, Th1 immunity and Th2 immunity approach a balance. But, the presence of tumor cells disrupts this balance. This occuring increased Th2 immunity and decreased Th1 immunity, because of down-regulation of adaptive immunity. This eventually leads to tumor progression. However, if Th1 immunity becomes predominant, this stimulation of immunity can lead to tumor regression.

https://researchgate.net/figure/Effects-of-Th1-Th2-on-tumor-progression-Naive-T-cells-become-Th1-cells-or-Th2-cells_fig2_319208977

 

 


   
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johan
(@j)
Joined: 4 years ago
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@aliml2 thanks for elaborating and making the distinction between the active form of vitamin D (calcitriol) and the stored form, inactive, which is the vitamin D we use as supplements. I didn't tag the post properly.


   
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medline
(@aliml2)
Joined: 8 months ago
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@j You're welcome! My reply was actually quotes from Prof. Trevor Marshall's articles, which are detailed on his website.

https://mpkb.org/home/pathogenesis/vitamind

 


   
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