The Link Between Calcitriol and Anticancer Immunotherapy: Vitamin D as the Possible Balance Between Inflammation and Autoimmunity in the Immune-Checkpoint Blockade

Abstract

" We are thus inclined to hypothesize a proportionally better prognostic role respectively for normal basal vitamin D levels and for recovering levels after proper repletion in advanced cancer patients, compared with the worse prognosis of vitamin D deficient patients who are unable to raise their levels. Similarly, the possible predictive role of vitamin D status for response to CKI might follow this proportional strength " First draft submitted: 5 September 2017; Accepted for publication: 25 September 2017; Published online: 25 October 2017The advent of the new immunotherapy with immune-checkpoint inhibitors (CKI) is currently revolutionizing the world of oncology, both in the advanced and early cancer setting.After the approval of the anti-CTLA-4 antibody ipilimumab for the systemic treatment of metastatic melanoma, a cascade of subsequent therapeutic indications of further CKI took place for several advanced cancers during the last decade [1,2]. Likewise, anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies are currently in study for the adjuvant setting in several cancer types after the first positive data still coming from melanoma [2,3].The great challenge of immune-checkpoint blockade is still represented by the lack of consistent predictive factors. Despite the evidence of conditions favoring response to CKI, for instance mismatch repair deficiency [4], PD-L1 expression, high mutational burden, loss of function of genes involved in antigen presentation and IFN-γ signaling among many others [5,6], each of these represents an imperfect marker, whose negativity does not exclude a good response to immunotherapy. Several studies are still investigating potentially predictive biomarkers.The role of vitamin D blood levels (25[OH]D, calcidiol) has been largely explored in the field of cancer, ranging from the assessment of hypovitaminosis D in cancer patient populations to the investigation of the possible prophylactic role of vitamin D supplementation to prevent cancer, basing on the preclinical evidence of an antiproliferative effect of calcitriol [7,8]. On the other hand, it is well known that the role of the active form of vitamin D (1,25[OH] 2 D, calcitriol) and of vitamin D receptor (VDR) is crucial for the proper activation of the immune system, particularly for T-cell differentiation and their effector function [9]. This evidence, in our opinion, constitutes the rationale for a possible pivotal link between vitamin D and the new anticancer immunotherapy with CKI, whose main goal is T-cell activation (Figure 1).Interestingly, most of immune cells express VDR and hold enzyme CYP27B1, used for the internal conversion of circulating 25(OH)D to the active VDR-ligand calcitriol. In fact, circulating levels of vitamin D are too low to affect immune responses in vivo and immune upregulation by calcitriol is dose dependent [9,10]. Not only antigen presenting cells such as monocytes, macrophages and dendritic cells, but also activated T cells are capable to produce 1,25(OH) 2 D in sufficiently high concentrations to ...

mTOR Links Tumor Immunity and Bone Metabolism: What are the Clinical Implications?

“…It has already been reported that VDR signaling is required for T cell activation and NKT cell development, both of which are important immunological factors for antitumor responses [44,45]. More recently, it has also been demonstrated that VD decreases tumor growth and increases tumor infiltrating CD8+ T cells in breast cancer [46].…”

A New Role for Vitamin D: The Enhancement of Oncolytic Viral Therapy in Pancreatic Cancer

“…Historically, pancreatic ductal adenocarcinomas have not responded well to monotherapy with immune checkpoint inhibitors when tested in clinical trials [75,76] and this is at least in part due to the poor immunogencity and decreased immune cell infiltrates of these tumors [77]. Vitamin D functions not only as a stromal reprogrammer, but it also modulates the immune system and plays a role in T cell activation, which may alter the tumor microenvironment to make checkpoint inhibitors more efficacious [78,79]. Multiple clinical trials (Table 1) are currently exploring the combination of immune checkpoint inhibitors and Vitamin D analogs (with and without other chemotherapeutics) for the treatment of pancreatic cancer.…”

Psychometric Validation of the EORTC QLQ-HCC18 in Patients with Previously Treated Unresectable Hepatocellular Carcinoma

“…Patients participating in BGB-A317-208 were treated with tislelizumab, a humanized immunoglobulin G4 (IgG)variant monoclonal antibody affecting the immune checkpoint-inhibitory receptor known as programmed cell death protein-1 (PD-1) [15,16]. The BGB-A317-208 context of use was distinct from the published QLQ-HCC18 validation population, with the former consisting of previously treated, unresectable HCC patients.…”