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
Nutrients 2021, 13(6), 1987; https://doi.org/10.3390/nu13061987
by Makoto Morita 1,2,Mai Okuyama 1,Taisuke Akutsu 1,Hironori Ohdaira 3,Yutaka Suzuki 3 and Mitsuyoshi Urashima 1,*OrcID
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
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.
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