Vitamin D might be fighting some cancers by increasing good microbiota – May 2024

Vitamin D-dependent microbiota-enhancing tumor immunotherapy

Cell Mol Immunol. 2024 May 31. doi: 10.1038/s41423-024-01184-4 behind paywall, can be read in DeepDyve
José M Izquierdo 1

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The antitumor immune response plays a crucial role in successful cancer treatment In a recent article in Science, Giampazolias et al. [1] reported a vitamin D (VitD)-mediated antitumor mechanism in murine intestinal epithelial cells (lECs) associated with a specific microbiota signature (Bacteroides fragilis) that enhances the anti­tumor immune response. The strong positive association between VitD-dependent microbiota and the antitumor immune response provides a proof-of-concept for supplementing immunotherapy regimens with VitD to strengthen antitumor immunity and improve immunotherapy success.

Unlike traditional treatments, immunotherapy does not target the cancer itself but instead trains the immune system to fight cancer. Several types of immunotherapies, including T-cell transfer therapy, immune system modulators, vaccines, mono­clonal antibodies, and immune checkpoint inhibitors (ICIs), are now approved for the treatment of many cancer types. Unfortunately, despite clinical success, only a subset of patients respond to immunotherapy (https://www.cancer.gov/about- cancer/treatment/types/immunotherapy) (Fig. 1).

The microbiota (or microbiome) refers to the populations of microorganisms that reside throughout the human body in different niches, such as the oral cavity, esophagus, lungs, stomach, skin, and gut [2]. Recent advances have demonstrated the key role of the microbiota in the diagnosis, development, and treatment of many diseases, including malignancies [2, 3].

In fact, nearly 20% of malignant cancers are associated with microbial infections [4]. Modulation of the microbiota is a promising tool for improving immunotherapy efficacy. The mechanisms underlying these effects are unknown but are likely to involve immune responses and microbiota-modified/derived metabolites [2].

Humans and other mammals can obtain vitamins from their diet or other external sources, or they can be derived/produced by the gut microbiota, and their production is regulated by the bidirectional crosstalk between the immune system and the gut microbiome. One vitamin that influences gut microbiota diversity and immune system regulation is VitD (Fig. 1A) [5]. VitD (calciferol) is produced by the skin via an ultraviolet light- dependent photolytic process as VitD2 (ergocalciferol from ergosterol) and VitD3 (cholecalciferol from 7-dehydrocholesterol) and from the diet (20% of total requirements). VitD2 and VitD3 are converted by at least five enzymes in the liver to the inactive prohormone 25-hydroxycholecalciferol (25-(OH)D3), which is hydroxylated by CYP27B1 in the kidney to its active, circulating…

10 References
  1. Giampazolias E, Pereira da Costa M, Lam KC, Lim KKJ, Cardoso A, Piot C, et al. Vitamin D regulates microbiome-dependent cancer immunity. Science. 2024;384:428–37. - DOI - PubMed - PMC
  2. Hou K, Wu ZX, Chen XY, Wang J-Q, Zhang D, Xiao C, et al. Microbiota in health and diseases. Signal Transduct Target Ther. 2022;7:135. - DOI - PubMed - PMC
  3. Kandalai S, Li H, Zhang N, Peng H, Zheng Q. The human microbiome and cancer: a diagnostic and therapeutic perspective. Cancer Biol Ther. 2023;24:2240084. - DOI - PubMed - PMC
  4. Galeano Niño JL, Wu H, LaCourse KD, Kempchinsky AG, Baryiames A, Barber B, et al. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature. 2022;611:810–17. - DOI - PubMed - PMC
  5. Martens PJ, Gysemans C, Verstuyf A, Mathieu C. Vitamin D’s effect on immune function. Nutrients. 2020;12:1248. - DOI - PubMed - PMC
  6. Singh P, Rawat A, Alwakeel M, Sharif E, al Khodor S. The potential role of vitamin D supplementation as a gut microbiota modifier in healthy individuals. Sci Rep. 2020;10:21641. - DOI - PubMed - PMC
  7. Safadi FF, Thornton P, Magiera H, Hollis BW, Gentile M, Haddad JG, et al. Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. J Clin Invest. 1999;103:239–51. - DOI - PubMed - PMC
  8. Jin H, Li M, Jeong E, Castro-Martinez F, Zuker CS. A body–brain circuit that regulates body inflammatory responses. Nature. 2024. https://doi.org/10.1038/s41586-024-07469-y .
  9. Yousefzadeh MJ, Flores RR, Zhu Y, Schmiechen ZC, Brooks RW, Trussoni CE, et al. An aged immune system drives senescence and ageing of solid organs. Nature. 2021;594:100–5. - DOI - PubMed - PMC
  10. Ross JB, Myers LM, Noh JJ, Collins MM, Carmody AB, Messer RJ, et al. Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature. 2024;628:162–70. - DOI - PubMed

Connecting vitamin D, the microbiome and anticancer immunity – May 2024

Original article: Giampazolias. E. et al. Vitamin D regulates microbiome-dependent cancer immunity. Science 384. 428-437(2024)

Vitamin D has a role in immune modula- tion and in shapingcommensal microbial communities. Reis e Sousa and colleagues show that mice lacking Gc globulin (Gc mice), which regulates vitamin D avail­ability, display enhanced tumour resistance. Intriguingly, co-housed wild-type mice, as well as mice that receive a faecal transfer from Gch mice, also exhibit enhanced tumour immunity. The authors found that vitamin D alters gene expression in intestinal epithelial cells in such a way that they pro­mote the expansion of Bacteroidesfragilis at the expense of Preuorella species (both are part of the normal gut microbiota). In wild- type mice, supplementation with vitamin D, or oral gavage with B.fragilis, enhanced tumour immunity. A connection between vitamin Dandtumourimmunitywasalso found in humans, as analysis of a Danish database of 1.5 million individuals showed that low vitamin D levels correlated with increased cancer incidence. In patients with cancer, a gene signature indicative of vitamin D receptor activation correlated with increased survival and improved responses to immunotherapy. Overall, these results reveal a new angle of the relationship between vitamin D, cancer and the micro- biome, and highlight vitamin D as a potential determinant in antitumour immunity.

VITAMIN D REGULATES MICROBIOME-DEPENDENT CANCER IMMUNITY - April 2024

SCIENCE 25 Apr 2024 Vol 384, Issue 6694 DOI: 10.1126/science.adh7954 PDF behind paywall

Editor’s summary
The gut microbiome has been shown to modulate the response of cancer patients to therapy, but precisely how microbiota affect anticancer immunity is still being elucidated. Giampazolias et al. report that vitamin D bioavailability in mice influences the composition of the gut microbiome (see the Perspective by Franco and McCoy). After dietary manipulation, vitamin D levels were observed to affect gut bacteria, which in turn improved cancer immunotherapy and antitumor immunity. In humans, low vitamin D levels were correlated with tumor development, and gene signatures of vitamin D activity were associated with improved patient responses to immunotherapy. These findings highlight the connection between vitamin D and the immune system through gut bacteria and may have applications for improving cancer therapies. —Priscilla N. Kelly

Abstract
A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D–induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.
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