Vitamin D Supplements Reduces All-Cause Death Risk in Digestive Tract Cancer Patients with High PD-L1 Levels

Posted on: Sunday, June 9th 2024 at 3:00 am

Written By: 

GreenMedInfo Research Group

A groundbreaking study has uncovered vitamin D's potential to regulate a key immune system protein and dramatically reduce the risk of death in a subset of digestive tract cancer patients. The findings suggest vitamin D supplements could be selectively employed as a natural, low-cost way to improve survival based on patients' PD-L1 levels.

A recent study published in the journal Nutrients has shed new light on vitamin D's intricate relationship with the immune system and how it could be leveraged to enhance survival in patients with digestive tract cancers. The randomized, double-blind, placebo-controlled trial known as AMATERASU found that vitamin D supplementation significantly reduced the risk of death in patients with the highest blood levels of a protein called PD-L1.1

PD-L1, short for Programmed Death-Ligand 1, acts as an "immune checkpoint" that can suppress the body's natural anti-cancer immune response.2 Some cancer cells exploit this mechanism by expressing PD-L1 on their surface, effectively evading immune detection and destruction. In recent years, expensive immunotherapy drugs that block PD-L1 or its receptor PD-1 have shown promise in treating various cancers, but with risk of serious side effects.3

Vitamin D's Bimodal Effects on PD-L1 Levels

The AMATERASU trial included 417 patients with stage I-III digestive tract cancers who underwent surgery. Researchers measured blood levels of PD-L1 before and after patients received either 2000 IU/day of vitamin D3 supplements or placebo. Surprisingly, vitamin D had opposite effects on PD-L1 depending on patients' starting levels:

• In patients with the lowest 20% (Q1) of PD-L1, vitamin D significantly increased levels
• In the middle 60% (Q2-4) of PD-L1, vitamin D had no significant effect
• In patients with the highest 20% (Q5) of PD-L1, vitamin D significantly decreased levels

As the study authors note, "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."1 This finding demonstrates the nuanced way in which vitamin D interacts with the immune system.

The High PD-L1 Subgroup: 66% Lower Risk of Death with Vitamin D

Most strikingly, in the subgroup of patients with the highest quintile of PD-L1 (Q5), vitamin D supplementation was associated with a significant 66% lower risk of death compared to placebo (HR 0.34; 95% CI 0.12–0.92). No significant effect was observed in the middle or lower PD-L1 subgroups. The interaction between high PD-L1 and vitamin D remained significant after adjusting for potential confounding factors.

As the researchers explain, "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."1 In other words, for digestive cancer patients with elevated PD-L1, vitamin D supplements may provide a powerful survival advantage.

Harnessing Vitamin D's Potential in Cancer Treatment

This study provides compelling evidence that vitamin D supplements could be selectively employed to improve outcomes in digestive cancer patients based on PD-L1 levels. For patients with the highest PD-L1, optimizing vitamin D intake through inexpensive supplements could enhance survival - a natural alternative or adjunct to pricey and potentially toxic immunotherapy drugs. Patients with low PD-L1 may also benefit from vitamin D's immune-boosting effects.

However, since vitamin D did not significantly impact relapse risk, the authors hypothesize its survival benefits may stem from "keeping cancer tissue dormant by down-regulating serum PD-L1 levels."1 Further research is needed to elucidate the mechanisms and determine optimal vitamin D protocols. Testing PD-L1 levels could help personalize supplementation strategies.

While the study focused on digestive cancers, its implications may extend to other malignancies. Prior studies have linked higher PD-L1 to worse outcomes in various cancers.4 Vitamin D's ability to modulate PD-L1 could represent a broadly applicable tool to enhance immunotherapy and survival.

Advocating for an Integrative Approach

These findings underscore the importance of an integrative approach to cancer treatment that includes evidence-based natural therapies like vitamin D alongside conventional care when appropriate. Patients must be informed of all options, including low-cost, low-risk ones, to make empowered decisions about their treatment.

With further research to optimize protocols, vitamin D supplementation could become a valuable addition to the cancer-fighting arsenal, harnessing the body's innate mechanisms rather than relying solely on expensive pharmaceuticals with adverse effects. An ounce of prevention is worth a pound of cure, and the AMATERASU trial suggests we may already have some powerful cancer-preventing tools in our toolkit - we need only use them judiciously.

For more research on the therapeutic value of vitamin D, visit our database on the subject here.

For more research on natural ways to address digestive cancers, visit our gastric cancer section here, and colon cancer section here.

---

References

1. 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 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 Jun;13(6):1987. https://www.mdpi.com/2072-6643/13/6/1987

2. Boussiotis VA. Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. N Engl J Med. 2016 Nov 3;375(18):1767-1778. https://www.nejm.org/doi/10.1056/NEJMra1514296

3. Gong J, Chehrazi-Raffle A, Reddi S, Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer. 2018 Jan 23;6(1):8. https://jitc.biomedcentral.com/articles/10.1186/s40425-018-0316-z

4. Zhang Y, Cai P, Liang T, Wang L, Hu L. TIM-3 is a potential prognostic marker for patients with solid tumors: A systematic review and meta-analysis. Oncotarget. 2017 May 23;8(19):31705-31713. https://www.oncotarget.com/article/15954/text/