Vitamin D Status in Cancer Immunotherapy: A Key Factor for Improving Treatment Outcomes

Vikas P. Sukhatme, MD, ScD

Introduction

Recent research has revealed that a patient's vitamin D status appears to significantly impact immunotherapy treatment outcomes. Emerging evidence suggests that maintaining adequate vitamin D levels may enhance the efficacy of immune checkpoint inhibitors (ICIs) – particularly those targeting the PD-1/PD-L1 pathway.

What the Research Shows

Multiple studies involving thousands of patients across different cancer types have shown consistent benefits from maintaining adequate vitamin D levels during immunotherapy.

Timerman et al. (2017) demonstrated that vitamin D deficiency was associated with worse prognosis in metastatic melanoma patients, with a hazard ratio of 2.06 compared to vitamin D-sufficient patients. More strikingly, patients who were initially vitamin D deficient and unable to raise their levels had nearly five times worse outcomes (HR: 4.68) compared to those with consistently normal levels.

In a groundbreaking study, Galus et al. (2023) demonstrated that vitamin D supplementation in melanoma patients receiving anti-PD-1 therapy significantly improved objective response rates and prolonged progression-free survival compared to patients who did not receive supplementation. This interventional study provides some of the strongest evidence to date that correcting vitamin D deficiency can directly enhance immunotherapy efficacy.

Bersanelli et al. (2017) proposed a compelling rationale for this link, suggesting that vitamin D plays a critical role in T-cell activation – the immune cells targeted by checkpoint inhibitors. They explain that vitamin D receptor (VDR) signaling enhances phosphoinositide phospholipase C-γ1 (PLC-γ1) expression, a pivotal molecule in T-cell receptor signaling that promotes appropriate immune responses against tumors.

Karkeni et al. (2019) provided experimental evidence for this connection, demonstrating that vitamin D supplementation in a breast cancer mouse model decreased tumor growth and increased CD8+ T cell infiltration into tumors. They observed that these T cells exhibited a more active central/effector memory phenotype, which is considered optimal for anti-tumor activity.

The Biological Mechanisms

The link between vitamin D and immunotherapy efficacy centers on T-cell function:

  • Vitamin D's active form (calcitriol) binds to the vitamin D receptor (VDR) present in T cells and many other immune cells
  • This binding upregulates key components of the T-cell receptor (TCR) signaling pathway
  • TCR signaling is essential for T cells to recognize and respond to cancer cells
  • PD-1 inhibitors work by preventing tumor cells from deactivating these same T cells

Essentially, vitamin D may "prime" T cells to be more responsive to immunotherapy by enhancing their baseline activation state. When adequate vitamin D is present, T cells may be better equipped to infiltrate tumors and mount an effective anti-cancer response once the brakes are removed by checkpoint inhibitors.

Clinical Implications

The evidence suggests some practical approaches that might improve immunotherapy outcomes:

  • Monitor vitamin D levels in all patients receiving immunotherapy
  • Correct vitamin D deficiency before starting treatment when possible

The Bersanelli group initiated the PROVIDENCE study to systematically investigate whether vitamin D supplementation improves outcomes in patients receiving checkpoint inhibitors for advanced cancers. While results are pending, this ongoing work reflects growing clinical interest in optimizing this modifiable factor.

Questions and Considerations

Several important questions remain:

  • What is the optimal vitamin D level for immunotherapy response?
  • Does the timing of vitamin D supplementation relative to immunotherapy administration matter?
  • Could vitamin D status explain some of the variability in immunotherapy response rates?
  • How does vitamin D status interact with other known predictors like PD-L1 expression or tumor mutational burden?

Some researchers have raised the intriguing hypothesis that vitamin D may help balance immune activation against autoimmunity during checkpoint inhibitor therapy. This could potentially enhance efficacy while reducing immune-related adverse events, though more research is needed.

What This Means for Patients

If you are receiving immunotherapy for cancer, discussing your vitamin D status with your treatment team may be worthwhile:

  1. Ask about your vitamin D status and whether supplementation is appropriate
  2. Consider vitamin D testing before starting immunotherapy

While definitive clinical trial evidence is still being gathered, these practical steps involve minimal risk and could potentially improve your treatment outcomes. As with any supplement, vitamin D should be taken under medical supervision, as excessive amounts can cause problems.

References

  1. Bersanelli M, Leonetti A, Buti S. The link between calcitriol and anticancer immunotherapy: vitamin D as the possible balance between inflammation and autoimmunity in the immune-checkpoint blockade. Immunotherapy. 2017;9(14):1127-1131.
  2. Timerman D, McEnery-Stonelake M, Joyce CJ, et al. Vitamin D deficiency is associated with a worse prognosis in metastatic melanoma. Oncotarget. 2017;8(4):6873-6882.
  3. Karkeni E, Morin SO, Bou Tayeh B, et al. Vitamin D controls tumor growth and CD8+ T cell infiltration in breast cancer. Front Immunol. 2019;10:1307.
  4. Galus A, et al. Vitamin D supplementation increases objective response rate and prolongs progression-free time in patients with advanced melanoma undergoing anti-PD-1 therapy. J Immunother Cancer. 2023; 129:2047-2055.