Can a supplementation with vitamin D influence PD-L1 expression in gastrointestinal cancer?

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

reference

Morita M, Okuyama M, Akutsu T, Ohdaira H, Suzuki Y, Urashima M. Vitamin D Supplementation regulates the postoperative serum levels of PD-L1 in patients with gastrointestinal cancer and improves survival in the highest quintile from PD-L1: A Post Hoc analysis of the randomized controlled study. nutrients . 2021; 13 (6): 1987.

Study goal

It should be examined whether a vitamin D supplementation regulates the ligands 1 (PD-L1) for programmed cell death in serum and thus could change the survival time of patients with gastrointestinal cancer (GI)

draft

A post-hoc analysis of the Amaterasu study in Japan, which was a randomized, double-blind, placebo-controlled study that was carried out at a single university hospital

participant

The study recruited patients aged 30 to 90 with cancer in stage I to III of the digestive tract from the esophagus to the rectum that were surgical candidates. Of the 439 suitable patients, 15 rejected and 7 were excluded after the operation. The test doctors closed all 417 randomized patients (average age 66 years; male 66 %; esophageal cancer of 10 %; gastric cancer 42 %) in the analysis to compare the effects of vitamin D _{3 dietary supplement (2,000 IE/day) and placebo in relapse and/or death in one relationship between 3: 2 between January 2010 and February 2018.}

The study included stomach cancer patients (44 %of participants), II (26 %) or III (30 %) who underwent a curative operation with complete tumor resection. Only those who have not yet taken vitamin D preparations were included.

Intervention

The test doctors randomized the patients in order to obtain additional oral vitamin D capsules (2,000 IE/day; n = 251) or placebo (n = 166) from the first postoperative visit to the end of the study. Placebo contained sesame oil, gelatin (from the pig) and glycerin, and the active supplement contained the same components plus vitamin d 3

study parameters evaluated

The researchers measured the postoperative serum PD-L1 mirror with Elisa and divided them into quintile (Q1-Q5). Serum samples were available from 396 (95.0 %) of the original study participants. The researchers collected serum samples for PD-L1 measurements after the operation (23 days, interquartile area (IQR): 13–43.5 days) and shortly before the start of vitamin D/placebo supplement. They also measured the serum PD L1 levels 1 year after the start of the vitamin D/placebo supplement.

The analyzed subgroups had Serum-25 (OH) D levels from 0 to less than 20 ng/ml, 20 to 40 ng/ml and more than 40 ng/ml. Due to the low sample size for the group with the highest starting value, the researchers only tested interactions between the groups with low and medium output value on serum-25 (oh) d.

Primary result measurements

The primary endpoint was the recurrent survival, the time until recurrence or death. The result of relapse or death was confirmed by regular outpatient aftercare. The passed time until the relapse or death was calculated from the time of randomization (i.e. from the start of the study).

important knowledge

Vitamin D supplementation significant ( p = 0.0008) increased the 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 reduced ( p = 0.0001) PD-L1 level in the highest quintile of the PD-L1 serum mirror (Q5) and increased or lowered the PD-L1 levels in the middle quintile of PD-L1 (Q2–Q4).

In the highest quintile (Q5), significant effects of a vitamin D supplementation were observed compared to placebo on death (HR, 0.34; 95 %-KI, 0.12–0.92) and relapse/death (HR, 0.37; 95 %-KI, 0.15–0.89). from serum-PD-L1, while significant effects in other quintils have not been observed (P _{interaction interaction = 0.04 for relapse/death).}

A vitamin D supplement significantly reduced the relapse and/or risk of death by about two thirds in the highest quintile of the serum PD-L1.

practice implications

Cancer immunotherapy has been a rapidly progressing research area in the past ten years, with the first checkpoint inhibitor, ipilimumab, which was approved in 2011 by the Food and Drug Administration (FDA) for the treatment of melanoma. was approved with advanced or inoperable melanoma. ^{2 From 2021, Checkpoint inhibitors are probably the best known and perhaps most successful immune modulators that have been developed so far, and have revolutionized oncology by improving the results and survival of many cancer patients. Checkpoint inhibitors have expanded our understanding of the complexity of immune function, especially with regard to cancer cells. The inhibitory checkpoint paths of our immune system are crucial to ensure that we maintain the self-tolerance (and prevent autoimmunity). However, we now know that tumore immun checkpoint signal paths use to escape the detection through the immune system. 4}

It seems advisable to continue to test the 25 (OH) D serum mirror for all cancer patients and to bring those with a defect to a healthy area.

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

We now know that the PD-1/PD-L1 signal path controls the initiation and maintenance of the immune tolerance within the micro environment of the tumor. ^{5 In addition to activated immune cells, PD-1 is also strongly expressed on tumor-specific T cells. T cells and B cells, dendritic cells and some epithelial cells expressed, especially under inflammatory conditions. 7 In addition, PD-L1 is expressed by tumor cells as "adaptive immun mechanism" in order to avoid antitumor reactions and to activate signal paths for proliferation and survival. PD-L1 is also involved in the later tumor progression.}

A current meta-analysis with a total of 21 studies showed that increased PD-L1 levels in the serum were accompanied by a poorer survival of cancer patients. ^{10 In particular, it was shown that a higher postoperative, but not preoperative total PD-L1 value in plasma in addition to exosomal PD-L1 with bad survival in patients is associated. 11 The theory is set up that in addition to checkpoint inhibitors, the reduction of the serum PD L1 levels after an operation could be a strategy to improve the survival of cancer patients.}

The vitamin D signal transmission was increasingly examined for its role in stimulating the innate immunity and the suppression of inflammatory reactions. Hormonal 1,25-dihydroxyvitamin D (1.25D) is a direct transcription induction inductor of the human genes that coded PD-L1 and PD-L2 via the vitamin D receptor (VDR). Quintil (Q1; the patients with the lowest PD-L1 output value values). In contrast, vitamin D supplementation reduced the serum PD L1 levels in the highest quintile (Q5). Thus, vitamin D seems to serve as a modifier of the biological reaction by increasing to increase serum PD-L1 when the serum PD L1 levels are low and serum PD-L1 when the Serum PD L1 levels are high. ¹³

In this study, vitamin D supplementation compared to placebo reduced the risk of death or death or death significantly to about a third in the highest quintile (Q5) of the serum PD-L1, but not to other quintile (ie Q1-Q4 of the PD-L1 level). The authors found that a vitamin D supplementation mainly reduces the risk of a complete death, and put the hypothesis that at least partially by improving the anti-cancer immunity and possibly by regulating the Serum PD L1 level by downright the cancer tissue came into being.

The connection between vitamin D and cancer has been examined for many years, and the data was temporarily positive, temporarily contradictory and temporarily without connection. ^{14 From the results of these and other studies it shows that there is a significant interaction between vitamin D and genetic expression of PD-L1 and that further research is required to examine the exact parameters of this relationship before specific clinical strategies can create. However, it seems advisable to continue to test the 25 (OH) D serum mirror for all cancer patients and to bring those with a defect into a healthy area.}

It should be pointed out that the results of this study may be transferable to other patient populations. There are several restrictions in this study: the study was carried out in Japan and all patients were Asian descent; The esophageal carcinomas were squamous cell carcinomas; And the incidence of stomach cancer is relatively high compared to other patient populations.