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30 augustus 2021: Bron: Nutrients 2021, 13(6), 1987; 
Received: 9 May 2021 / Revised: 1 June 2021 / Accepted: 5 June 2021 / Published: 9 June 2021

Vitamine D3-suppletie gegeven aan patiënten die waren geopereerd aan een vorm van spijsverteringskanker, in de studie waren patiënten met slokdarmkanker, maagkanker, darmkanker en endeldarmkanker opgenomen, verminderde met ongeveer een derde het risico op een recidief en op overlijden bij de groep van patiënten die in de basis de hoogste bloedwaarden van PD-L1 hadden. In de groepen patiënten met gemiddelde normale waarden en te lage waarden werd geen statistisch significant verschil gezien in kans op recidief of overlijden.

Patiënten die te hoge PD-L1 waarden hadden zakten door de vitamine D3 suppletie naar normale waarden. Bij patiënten die te lage waarden hadden stegen de bloedwaarden PD-L1 naar normale waarden. De vitamine D3 suppletie reguleerde dus de bloedwaarden PD-L1 tot een normaal niveau voor PD-L1 waarden. 

Conclusie van de onderzoekers:

Vitamine D-suppletie kan, in vergelijking met placebo, bimodale functies hebben om de serum-PD-L1-waarden te verhogen wanneer de serum-PD-L1-spiegels te laag zijn en om de serum-PD-L1-spiegels te verlagen wanneer de serum-PD-L1-spiegels te hoog zijn. Vitamine D-suppletie, vergeleken met placebo, verminderde het risico op overlijden door alle oorzaken, evenals op terugval of overlijden, significant tot ongeveer een derde in het hoogste kwintiel (Q5), maar niet in andere quintielen, d.w.z. Q1-Q4. Verdere studies zijn nodig om de mechanismen van de bimodale functie van vitamine D in de secretie van serum PD-L1 te onderzoeken om potentiële therapeutische mogelijkheden te ontwikkelen door suppletie van vitamine D.

Deze resultaten komen uit een gerandomiseerde placebo gecontroleerde fase III studie bij totaal 417 patiënten met kanker van het spijsverteringskanaal, van de slokdarm tot het rectum.

De AMATERASU 5 studie is opgezet om de effecten van vitamine D3-supplementen (2000 IE/dag) en placebo op een recidief en/of overlijden te vergelijken. De deelnemende patiënten met een indeling in een verhouding van 3:2 werd uitgevoerd in het International University of Health and Welfare Hospital (Otawara, Tochigi, Japan) in de periode tussen januari 2010 en februari 2018.

Een klein stukje uit de introductie van de studie vrij vertaald:

Programmed death-ligand 1 (PD-L1) is vooral bekend door de vormen van immuuntherapie die met zogeheten anti-PD medicijnen worden gegeven. Maar de PD-L1 wordt ook tot expressie gebracht op een deel van de kankercellen om de immuniteit tegen kanker te onderdrukken door interactie met de geprogrammeerde death-1 (PD-1) receptor die tot expressie wordt gebracht op immuuncellen. [1]. Het blokkeren van deze interactie door het toedienen van monoklonale antilichamen die gericht zijn op de PD-1- of de PD-L1-molecuul verbetert inderdaad de prognose van patiënten met kanker, althans gedeeltelijk. [2]. 

Omdat eerder in studies is gevonden dat vitamine D-responsieve elementen zich in het PD-L1-gen bevinden, werd verondersteld dat vitamine D-suppletie de serum-PD-L1-spiegels zou reguleren en dus de overlevingstijd van kankerpatiënten zou veranderen.

Daarom werd de AMATERASU 5 studie opgezet. Met dus heel verrassende resultaten waarbij vitamine D3 als het ware als een vorm van immuuntherapie bleek te werken voor die patiënten die afwijkende PD-L1 bloedwaarden hadden.

Hier de opzet van de studie in een grafiek verwerkt.

Nutrients 13 01987 g001 550


En hier de grafieken van de PD-L1 waarden voor en na de start met de vitamine D3 suppletie.

3.3. Serum PD-L1 Levels before and after Starting Supplements

Serum PD-L1 levels were assessed in 396 patients (Figure 2A). The median (IQR) level was 55.5 (44.2–70.2) pg/mL, with the distribution skewed to the right. Strong associations between serum PD-L1 levels before and after starting supplements were observed in the total sample (Figure 2B), in the vitamin D group (Figure 2C), and in the placebo group (Figure 2D).
Nutrients 13 01987 g002 550
Figure 2. Histogram of serum PD-L1 levels (A). Scatter plot between pre serum PD-L1 and post serum PD-L1 levels in all patients (B), in the vitamin D group (C), and in the placebo group (D). Spearman’s rank correlation coefficient (RHO) was used to quantify the strength of the association. The equation was calculated by linear regression analysis.


Het studierapport is verder heel gedetailleerd met heldere grafieken en beschrijvingen en gratis in te zien met ook een interessante referentielijst. Klik op de titel van het abstract om het studierapport in te zien of te downloaden.


Vitamin D Supplementation Regulates Postoperative Serum Levels of PD-L1 in Patients with Digestive Tract Cancer and Improves Survivals in the Highest Quintile of PD-L1: A Post Hoc Analysis of the AMATERASU Randomized Controlled Trial

by 
Makoto Morita
 1,2,
Mai Okuyama
 1,
Taisuke Akutsu
 1,
Hironori Ohdaira
 3,
Yutaka Suzuki
 3 and
mitsuyoshi Urashima1
,*
1
Division of Molecular Epidemiology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo 105-8461, Japan
2
Pfizer Japan Inc., Shinjuku Culture Quint Bldg, 3-22-7 Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan
3
Department of Surgery, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi 329-2763, Japan
*
Author to whom correspondence should be addressed.
Nutrients 2021, 13(6), 1987; https://doi.org/10.3390/nu13061987
Received: 9 May 2021 / Revised: 1 June 2021 / Accepted: 5 June 2021 / Published: 9 June 2021
(This article belongs to the Section Nutritional Immunology)
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Abstract

Because vitamin D responsive elements have been found to be located in the PD-L1 gene, vitamin D supplementation was hypothesized to regulate serum PD-L1 levels and thus alter survival time of cancer patients. A post hoc analysis of the AMATERASU randomized, double-blind, placebo-controlled trial of postoperative vitamin D3 supplementation (2000 IU/day) in 417 patients with stage I to stage III digestive tract cancer from the esophagus to the rectum was conducted. Postoperative serum PD-L1 levels were measured by ELISA and divided into quintiles (Q1–Q5). Serum samples were available for 396 (95.0%) of the original trial. Vitamin D supplementation significantly (p = 0.0008) up-regulated serum PD-L1 levels in the lowest quintile (Q1), whereas it significantly (p = 0.0001) down-regulated them in the highest quintile (Q5), and it did not either up- or down-regulate them in the middle quintiles (Q2–Q4). Significant effects of vitamin D supplementation, compared with placebo on death (HR, 0.34; 95% CI, 0.12–0.92) and relapse/death (HR, 0.37; 95% CI, 0.15–0.89) were observed in the highest quintile (Q5) of serum PD-L1, whereas significant effects were not observed in other quintiles (Pinteraction = 0.02 for death, Pinteraction = 0.04 for relapse/death). Vitamin D supplementation significantly reduced the risk of relapse/death to approximately one-third in the highest quintile of serum PD-L1.



 

4. Discussion

In this clinical study, vitamin D supplementation up-regulated serum PD-L1 levels in the lowest quintile (Q1). This seems to be consistent with the results of experimental research that showed that vitamin D up-regulated expression of PD-L1 in epithelial and myeloid cells [13]. In contrast, vitamin D supplementation down-regulated serum PD-L1 levels in the highest quintile (Q5). Thus, vitamin D may have bimodal functions to increase serum PD-L1 when the serum PD-L1 levels are too low and to decrease serum PD-L1 when the serum PD-L1 levels are too high. However, further research regarding regulation of PD-L1 expression by vitamin D supplementation is needed.
Vitamin D supplementation, compared with placebo, significantly reduced the risk of total death, as well as relapse or death, to one-third in the highest quintile (Q5), but not in other quintiles, i.e., Q1–Q4, and did not change the risk of relapse. Because serum PD-L1 levels increased in an age-dependent manner in the present study and a previous report [19], multivariate adjustment including age was done and showed that they remained significant. In the present study, effects of the interaction between vitamin D and the highest quintile of serum PD-L1 were observed for the outcome of death rather than of relapse. Immune checkpoint inhibitors seem to improve overall survival rather than progression-free survival [20,21,22]. However, how PD-L1 is associated with death rather than relapse of patients has not yet been elucidated. Both the SUNSHINE [23] and AMATERASU [14] trials did not show significance in the primary results, although recent meta-analyses of RCTs suggested that vitamin D supplementation improved the survival of patients with cancer [24,25,26,27]. It has been hypothesized that vitamin D supplementation mainly reduces the risk of total death, at least in part by enhancing anti-cancer immunity and perhaps by keeping cancer tissue dormant by down-regulating serum PD-L1 levels.
This study has several limitations. First, exosomal PD-L1 was not measured in this study. However, not only exosomal PD-L1, but also total plasma PD-L1 was strongly associated with survival of patients with gastric cancer [10]. Second, serum PD-L1 levels were measured only after operation, but not before operation. However, postoperative rather than preoperative levels were reported to be associated with survival of patients with cancer [10]. Third, this study performed an exploratory analysis that was not pre-specified in the original protocol of the AMATERASU trial and must, therefore, be interpreted with caution. Fourth, subgroup analyses of quintiles may increase the probability of type I error due to multiple comparisons. A recent guideline for statistical reporting recommends replacing p values with estimates of effects, such as HR and 95% CIs, when neither the protocol nor the statistical analysis plan has specified methods used to adjust for multiplicity [28]. Thus, p values were avoided in the present study, except for calculating p values for interaction and for changes in serum PD-L1 levels; instead, 95% CIs were used to determine significance. Fifth, because the AMATERASU trial was conducted in Japan, the patients were Asian, most esophageal cancers were squamous cell carcinomas, the incidence of gastric cancer was still relatively high, and the optimal levels of total 25(OH)D and bioavailable 25(OH)D could be different from those in other population groups. Thus, the results of the present study are not necessarily generalizable to other populations. Sixth, the study population included patients with a mixture of cancers with biological and clinical differences.

5. Conclusions

Vitamin D supplementation, compared with placebo, may have bimodal functions to increase serum PD-L1 when the serum PD-L1 levels are too low and to decrease serum PD-L1 levels when the serum PD-L1 levels are too high. Vitamin D supplementation, compared with placebo, significantly reduced the risk of all-cause death, as well as relapse or death, to approximately one-third in the highest quintile (Q5), but not in other quintiles, i.e., Q1-Q4. Further studies are needed to explore the mechanisms of bimodal function of vitamin D in the secretion of serum PD-L1 in order to develop potential therapeutic opportunities by supplementation of vitamin D.

Author Contributions

Conceptualization, M.U.; methodology, M.M. and M.O.; formal analysis, M.M., and M.U.; resources, H.O. and Y.S.; data curation, T.A.; writing—original draft preparation, M.M. and M.U.; writing—review and editing, M.O., T.A., H.O. and Y.S.; funding acquisition, M.U. and M.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Education, Culture, Sports, Science, and Technology in the Japan-Supported Program for the Strategic Research Foundation at Private Universities, JSPS KAKENHI Grant Number 20H03537 (to M. Urashima), and the Jikei University Research Fund for Graduate Students (to M. Morita).

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the ethics committee of the International University of Health and Welfare Hospital (Otawara, Tochigi, Japan) (ethics approval code: 13-B-263), as well as the Jikei University School of Medicine (Nishi-shimbashi, Tokyo, Japan) (ethics approval code: 21-216 (6094)).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Publicly available datasets were analyzed in this study. This data can be found here: https://upload.umin.ac.jp/cgibin/icdr/ctr_menu_form_reg.cgi?recptno=R000002412 (accessed on 5 April 2019).

Acknowledgments

The authors would like to thank Masumi Chida and Tomomi Ishikawa for making tissue microarrays and staining at the Department of Pathology, International University of Health and Welfare Hospital (Otawara, Japan); Yasuko Otsuki as a clinical research coordinator at the International University of Health and Welfare Hospital (Otawara, Japan); and Haruka Wada for data management and data monitoring at the Division of Molecular Epidemiology, Jikei University School of Medicine (Tokyo, Japan).

Conflicts of Interest

Makoto Morita is employed by Pfizer Japan Inc., but this work was performed independent of his work for that company. The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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