Vitamin D3 treatment of tumor bearers can stimulate immune competence and reduce tumor growth when treatment coincides with a heightened presence of natural suppressor cells

Young, Matthew R.; Lozano, Yvonne; Ihm, Joe; Wright, M. A.; Prechel, Margaret

doi:10.1016/0304-3835(96)04241-3

Cited by 29 publications

(9 citation statements)

References 32 publications

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“…35,36 Since then, studies in animals have shown the beneficial effects of 1,25(OH 2 )D 3 in reducing cancer progression. [37][38][39][40] However, the associations between Vitamin D and sunshine exposure and colorectal cancer are mixed, with inverse associations generally observed, although often not reaching statistical significance. 10,13 In our study, we observed stronger associations with vitamin D intake and sunshine exposure for colon cancer in men if they also had 23 or more CAG repeats of the AR gene.…”

Section: Discussionmentioning

confidence: 99%

Associations between vitamin D, vitamin D receptor gene and the androgen receptor gene with colon and rectal cancer

Slattery

Sweeney

Murtaugh

et al. 2006

Intl Journal of Cancer

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The transcriptional activity of the vitamin D receptor (VDR) gene is regulated, at least in part, by the androgen receptor (AR) gene. We evaluate how the number of polyglutamine (CAG) repeats of the AR gene influence colorectal cancer in conjunction with vitamin D, sunshine exposure and VDR. Studies of colon (1,580 cases and 1,968 controls) and rectal (797 cases and 1,016 controls) cancer were used. Vitamin D intake and average hours of sunshine exposure interacted with AR genotype in men. Men with low vitamin D intake or low levels of sunshine exposure who had 231 CAG repeats of the AR gene had the greatest risk of colon cancer. ORs for men with 23 or more CAG repeats of the AR gene and in the lowest tertile of vitamin D intake or sunshine exposure were 1.71 (95% CI 1.14, 2.56) and 1.51 (95% CI 1.09, 2.09). Men with high levels of sunshine exposure were at reduced risk of developing rectal cancer if they had 23 or more CAG repeats (OR 0.62 95% CI 0.39, 0.97) than if they had fewer than 23 CAG repeats. The FF genotype of the Fok1 VDR gene was associated with reduced risk of colon cancer among women with any allele of 231 CAG repeats (OR 0.62 95% CI 0.44, 0.88), whereas men with the LL/bb VDR genotypes were at reduced risk of rectal cancer if they also had 231 CAG repeats (OR 0.71 95% CI 0.48, 1.05) relative to men with fewer than 23 CAG repeats of the AR gene. These data provide support for the role of vitamin D and sunshine exposure in the etiology of colorectal cancer and suggest that AR gene may modulate the association. Vitamin D has been associated inconsistently with colorectal cancer. 10 Differences in relative risk could stem from many sources, including sunshine, a major source of vitamin D, not being considered as part of the risk factor equation. Several investigators have studied sunshine exposure independently to better understand the associations between vitamin D and colorectal cancer. 11-13 Polymorphisms of the VDR gene have also been studied in conjunction with colorectal cancer and adenomas, since it may play a key role in vitamin D signaling, which could further influence colorectal cancer risk. [14][15][16][17][18][19] Polymorphisms of the VDR gene that have been studied include a poly A repeat at the 3 0 untranslated region (3 0 UTR) of the gene, 2 polymorphisms at intron 8 (Bsm I and Apa I) and 1 in exon 9 (Taq I) that are in linkage-disequilibrium with each other. 17,20 These polymorphisms, either alone or in combination, have been associated with increased mRNA expression of the VDR gene and increased serum levels of 1,25-dihydroxy vitamin D. 21,22 At the start site of the gene, a polymorphism detected with a Fok I digest has also been studied and has been shown to be not in linkage disequilibrium with the other variants. 17 A study conducted in human fibroblast cell lines found higher vitamin D hormone activity for the F allele than for the f allele. 23 One study showed that the ff genotype of the Fok I polymorphism increased risk of colorectal cancer, 18 whereas another showed that it w...

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Section: Discussionmentioning

confidence: 99%

Associations between vitamin D, vitamin D receptor gene and the androgen receptor gene with colon and rectal cancer

Slattery

Sweeney

Murtaugh

et al. 2006

Intl Journal of Cancer

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“…This has been achieved with limited success in preclinical mouse models through the administration of all-trans-retinoic acid (ATRA), interferon (IFN)-γ or vitamin D3 [45][46][47]. Treatment of renal cell carcinoma patients with ATRA was also found to enhance their immune responses and myeloid cell differentiation [48].…”

Section: Myeloid-derived Suppressor Cellsmentioning

confidence: 99%

Improving cancer immunotherapy by targeting tumor-induced immune suppression

Stewart

Smyth

2011

Cancer Metastasis Rev

132

107

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The status of a host's immune response influences both the development and progression of a malignancy such that immune responses can have both pro- and anti-tumorigenic effects. Cancer immunotherapy is a form of treatment that aims to improve the ability of a cancer-bearing individual to reject the tumor immunologically. However, antitumor immunity elicited by the host or by immunotherapeutic strategies, can be actively attenuated by mechanisms that limit the strength and/or duration of immune responses, including the presence of immunoregulatory cell types or the production of immunosuppressive factors. As our knowledge of tumor-induced immune suppression increases, it has become obvious that these mechanisms are probably a major barrier to effective therapy. The identification of multiple mechanisms of tumor-induced immune suppression also provides a range of novel targets for new cancer therapies. Given the vital role that a host's immune response is known to play in cancer progression, therapies that target immune suppressive mechanisms have the potential to enhance anticancer immune responses thus leading to better immune surveillance and the limitation of tumor escape. In this review, mechanisms of tumor-associated immune suppression have been divided into four forms that we have designated as (1) regulatory cells; (2) cytokines/chemokines; (3) T cell tolerance/exhaustion and (4) metabolic. We discuss select mechanisms representing each of these forms of immunosuppression that have been shown to aid tumors in evading host immune surveillance and overview therapeutic strategies that have been recently devised to "suppress these suppressors."

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“…Furthermore, all-trans retinoic acid differentiates MDSCs into mature dendritic cells, macrophages, and granulocytes, which increase responses to cancer vaccines. In contrast, 1a,25-dihydroxyvitamin D3 has an indirect action via a reduction in myelopoiesis (66). Low doses of IFN-g and tumor necrosis factor can also reduce MDSC number by inducing cellular differentiation (67).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Pathways Mediating the Expansion and Immunosuppressive Activity of Myeloid-Derived Suppressor Cells and Their Relevance to Cancer Therapy

Talmadge

2007

Clinical Cancer Research

244

215

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Cancer immunotherapy has focused on inducing and expanding CTLs and improving the immune recognition of weak antigenic determinants expressed by tumors. However, few positive clinical outcomes have been reported due, in part, to tumor-associated immunologic tolerance, supporting the need for an emphasis on overcoming immunosuppression. Systemic immunosuppression is associated with abnormal myelopoiesis secondary to tumor growth, myelosuppressive therapy, and growth factor administration and subsequent expansion/mobilization of bone marrowd erived immunosuppressive cells. These myeloid-derived suppressor cells (MDSC) reduce activated T-cell number and inhibit their function by multiple mechanisms, including depletion of L-arginine by arginase-1 (ARG1) production of nitric oxide, reactive oxygen species, and reactive nitrogen oxide species by inducible nitric oxide synthase. Increased numbers of MDSCs are associated with neoplastic, inflammatory, infectious, and graft-versus-host diseases where they restrain exuberant or novel T-cell responses. In this review, we discuss critical components of MDSC-mediated suppression of T-cell function, including cellular expansion and activationinduced secretion of immunosuppressive mediators. Both components of MDSC bioactivity are amenable to pharmacologic intervention as discussed herein. We also focus on the relationship between MDSCs, tumor growth, therapeutic responses, and the mechanisms of cellular expansion, activation, and immunosuppression.Host immunity has a critical role in regulating tumor outgrowth and patient survival; however, the expansion of tumor-specific T cells is also limited by tumor growth. Recently, there has been a resurgence of interest in myeloid-derived cells in association with their role in tumor progression and potential to limit therapeutic responses. Myeloid-derived suppressor cells (MDSC) are increased in numerous pathologic conditions, including infections, inflammatory diseases, graft-versus-host disease, traumatic stress, and neoplastic diseases (1, 2), and serve to limit T-cell responses. Tumor growth results in the expansion of this highly heterogeneous cellular population, which includes granulocytic, macrophage, dendritic cell, and early myeloid progenitors. MDSCs inhibit not only activation of T cells by anti-CD3 and superantigen, but also antigen-specific CD4 + and CD8 + T-cell responses. The mechanisms of MDSC immunosuppression are diverse, including up-regulation of reactive oxygen species (ROS), nitric oxide (NO), and L-arginine metabolism, as well as immunosuppressive cytokines. MDSCs were initially described in the late 1970s when they were identified as natural suppressor cells and defined as cells without lymphocyte-lineage markers that could suppress lymphocyte response to immunogens and mitogens (3 -5). MDSCs in mice are CD11b and Gr1 positive (6, 7) and also express CD31 (8), CD124, interleukin (IL)-4 receptor a-chain (9) and CD115, and macrophage-colony stimulating factor receptor (10). Human MDSC equivalents we...

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Vitamin D3 treatment of tumor bearers can stimulate immune competence and reduce tumor growth when treatment coincides with a heightened presence of natural suppressor cells

Cited by 29 publications

References 32 publications

Associations between vitamin D, vitamin D receptor gene and the androgen receptor gene with colon and rectal cancer

Associations between vitamin D, vitamin D receptor gene and the androgen receptor gene with colon and rectal cancer

Improving cancer immunotherapy by targeting tumor-induced immune suppression

Pathways Mediating the Expansion and Immunosuppressive Activity of Myeloid-Derived Suppressor Cells and Their Relevance to Cancer Therapy

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