Can vitamin D supplementation affect PD-L1 expression in gastrointestinal cancer?

This article is part of our October 2021 special issue. Download the full issue here.

Relation

Morita M, Okuyama M, Akutsu T, Ohdaira H, Suzuki Y, Urashima M. Vitamin D supplementation regulates postoperative serum levels of PD-L1 in patients with gastrointestinal cancer and improves survival in the highest quintile of PD-L1: a post hoc analysis of the AMATERASU randomized controlled trial.Nutrients. 2021;13(6):1987.

Study objective

To investigate whether vitamin D supplementation regulates programmed cell death ligand 1 (PD-L1) in serum and thus could alter the survival of patients with gastrointestinal (GI) cancer

Draft

A post hoc analysis of the AMATERASU trial in Japan, which was a randomized, double-blind, placebo-controlled trial conducted at a single university hospital

Participant

The study recruited patients aged 30 to 90 years with stage I to III cancers of the digestive tract from the esophagus to the rectum who were surgical candidates. Of the 439 eligible patients, 15 declined and 7 were excluded after surgery. Investigators included all 417 randomized patients (mean age, 66 years; male, 66%; esophageal cancer, 10%; stomach cancer, 42%; colorectal cancer, 48%) in the analysis to compare the effects of vitamin D₃Supplements (2,000 IU/day) and placebo for relapse and/or death in an allocation ratio of 3:2 between January 2010 and February 2018.

The study included patients with stage I (44% of participants), II (26%), or III (30%) gastric cancer who underwent curative surgery with complete tumor resection. Only those who were not already taking vitamin D supplements were included.

intervention

Investigators randomized patients to receive supplemental oral vitamin D capsules (2,000 IU/day; n = 251) or placebo (n = 166) from the first postoperative outpatient visit until the end of the study. Placebo contained sesame oil, gelatin (porcine), and glycerin, and the active supplement contained the same ingredients plus vitamin D₃as 25-hydroxycholecalciferol, 25(OH)D.

Study parameters assessed

The researchers measured postoperative serum PD-L1 levels using ELISA and divided them into quintiles (Q1-Q5). Serum samples were available from 396 (95.0%) of the original study participants. Researchers collected serum samples for PD-L1 measurements after surgery (23 days, interquartile range (IQR): 13-43.5 days) and just before starting vitamin D/placebo supplementation. They also measured serum PD-L1 levels 1 year after starting vitamin D/placebo supplementation.

The subgroups analyzed had baseline serum 25(OH)D levels of 0 to less than 20 ng/ml, 20 to 40 ng/ml, and more than 40 ng/ml. Due to the small sample size for the highest baseline group, the researchers tested interactions only between the low and intermediate baseline serum 25(OH)D groups.

Primary outcome measures

The primary endpoint was recurrence-free survival, time to recurrence, or death. The outcome of relapse or death was confirmed by regular outpatient follow-up. Elapsed time to relapse or death was calculated from the time of randomization (ie, from the start of study supplementation).

Key insights

Vitamin D supplementation significant (P=0.0008) increased serum PD-L1 levels in the lowest quintile of PD-L1 (Q1; i.e. those patients who started with the lowest PD-L1 levels), while it significantly (P=0.0001) decreased PD-L1 levels in the highest quintile of serum PD-L1 levels (Q5) and did not increase or decrease PD-L1 levels in the middle quintile of PD-L1 (Q2–Q4).

In the highest quintile (Q5), 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. of serum PD-L1, while significant effects were not observed in other quintiles (P_interaction=0.02 for death, P_interaction=0.04 for relapse/death).

Vitamin D supplementation significantly reduced the risk of relapse and/or death by approximately two-thirds in the highest quintile of serum PD-L1.

Practice implications

Cancer immunotherapy has been a rapidly advancing area of ​​research over the past decade, with the first checkpoint inhibitor, ipilimumab, approved by the Food and Drug Administration (FDA) for the treatment of melanoma in 2011.¹Meanwhile, researchers studied the first PD-1 inhibitor, pembrolizumab, approved in 2014 for patients with advanced or unresectable melanoma.²As of 2021, checkpoint inhibitors are probably the best-known and perhaps most successful immunomodulators developed to date and have revolutionized oncology by improving the outcomes and survival of many cancer patients.³The mechanism of action and broad applicability of checkpoint inhibitors have expanded our understanding of the complexity of immune function, particularly as it relates to cancer cells. Our immune system's inhibitory checkpoint pathways are critical to ensuring we maintain self-tolerance (and prevent autoimmunity). However, we now know that tumors use immune checkpoint pathways to evade detection by the immune system.⁴

In the meantime, it seems prudent to continue testing serum 25(OH)D levels in all cancer patients and to bring those with deficiency into a healthy range.

During a healthy immune response, programmed cell death protein 1 (PD-1) serves to inhibit immune responses and promote self-tolerance by regulating the activity of T cells. Likewise, programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is a co-inhibitory factor of the immune response and is responsible for reducing the activity of PD-1 positive cells and inducing apoptosis.

We now know that the PD-1/PD-L1 pathway controls the initiation and maintenance of immune tolerance within the tumor microenvironment.⁵In addition to activated immune cells, PD-1 is also highly expressed on tumor-specific T cells.⁶PD-L1 is normally expressed by macrophages, some activated T cells and B cells, dendritic cells and some epithelial cells, especially under inflammatory conditions.⁷Furthermore, PD-L1 is expressed by tumor cells as an “adaptive immune mechanism” to evade antitumor responses and activate signaling pathways for proliferation and survival.⁸PD-L1 is also involved in subsequent tumor progression.⁹

A recent meta-analysis with a total of 21 studies showed that increased serum PD-L1 levels were associated with worse survival in cancer patients.¹⁰In particular, higher postoperative but not preoperative total plasma PD-L1 in addition to exosomal PD-L1 has been shown to be associated with poor survival in patients with gastric cancer.¹¹It is theorized that, in addition to checkpoint inhibitors, lowering serum PD-L1 levels after surgery could be a strategy to improve survival in cancer patients.

Vitamin D signaling has been increasingly investigated for its role in stimulating innate immunity and suppressing inflammatory responses. Hormonal 1,25-dihydroxyvitamin D (1,25D) is a direct transcription inducer of the human genes encoding PD-L1 and PD-L2 via the vitamin D receptor (VDR).¹²In this clinical trial, vitamin D supplementation increased serum PD-L1 levels in the lowest quintile (Q1; the patients with the lowest baseline PD-L1 levels). In contrast, vitamin D supplementation decreased serum PD-L1 levels in the highest quintile (Q5). Thus, vitamin D appears to serve as a biological response modifier by serving to increase serum PD-L1 when serum PD-L1 levels are low and to decrease serum PD-L1 when serum PD-L1 levels are high.¹³

In this study, compared with placebo, vitamin D supplementation significantly reduced the risk of all-cause death and relapse or death to approximately one-third in the highest quintile (Q5) of serum PD-L1, but not in other quintiles (i.e., Q1–Q4 of PD-L1 levels). The authors found that vitamin D supplementation mainly reduced the risk of complete death and hypothesized that this was at least in part by improving anticancer immunity and possibly by downregulating serum PD-L1 levels by downregulating quiescent cancer tissue.¹³

The connection between vitamin D and cancer has been studied for many years, and the data has been at times positive, at times conflicting, and at times unrelated.¹⁴It is clear from the results of this and other studies that there is a significant interaction between vitamin D and the genetic expression of PD-L1 and that further research is needed to examine the precise parameters of this relationship before specific clinical strategies can be created. However, in the meantime, it seems prudent to continue testing serum 25(OH)D levels in all cancer patients and to bring those with deficiency into a healthy range.

It should be noted that the results of this study may or may not be generalizable to other patient populations. There are several limitations to this study: the study was conducted in Japan, and all patients were of Asian descent; the esophageal carcinomas were squamous cell carcinomas; and the incidence of gastric cancer is relatively high compared to other patient populations.