Mediterranean Diet Correlates With Responses to Melanoma Immunotherapy


Previous research has identified a link between nutrients commonly found in a Mediterranean diet such as fiber, unsaturated fats, antioxidants, and polyphenols, and immunomodulatory/anti-tumor activities, according to a dietician from the University of Groningen.

A habitual Mediterranean diet may have a role in improving responses to immune checkpoint blockade as therapy for advanced melanoma, according to findings from a cohort study published in JAMA Oncology.

"We need larger studies across multiple geographies to further elucidate the role of diet in the context of cancer immunotherapy," according to a dietician from the University of Groningen.

"We need larger studies across multiple geographies to further elucidate the role of diet in the context of cancer immunotherapy," according to a dietician from the University of Groningen.

An alternative Mediterranean diet positively correlated with progression-free survival at 12 months (PFS-12; probability of 0.74; P = .01; false discovery rate [FDR], .021; effective degrees of freedom [edf], 1.54) as well as overall response rate (ORR; probability of 0.77; P = .02; FDR, .032; edf, 0.83).

“A Mediterranean dietary pattern is associated with positive responses to immune checkpoint blockade, a relatively new and successful treatment against severe cancers,” lead author Laura A. Bolte, MSc, a dietician and MD/PhD candidate of the Department of Gastroenterology and Hepatology at the University of Groningen and University Medical Center Groningen in the Netherlands, stated in a written comment to CancerNetwork®. “These [immune checkpoint blockade] drugs cause the immune system to recognize, clear and destroy cancer cells.”

Bolte elaborated on the potential health benefits associated with a Mediterranean diet.

“These foods are important sources of fiber, unsaturated fats, antioxidants, and polyphenols. Preclinical and functional studies have shown immunomodulatory and anti-tumor activities of these nutrients—in part mediated via the gut microbiome,” Bolte stated.

Investigators of this cohort study evaluated the association between habitual diet and responses to treatment with immune checkpoint blockade for advanced melanoma. Investigators prospectively gathered clinical and dietary data from patients enrolled in the PRIMM-UK trial (NCT03643289) and the PRIMM-NL/POINTING trial (NCT04193956).

Clinical end points of interest included ORR, PFS at 12 months, and immune-related adverse effects (IRAEs). Investigators assessed IRAEs based on CTCAE v5.0 criteria, focusing on grade 2 or higher incidence to avoid the interindividual variability associated with the mildest of AEs.

Investigators evaluated dietary intake through the EPIC-Norfolk food frequency questionnaire and the Dutch Healthy Diet food frequency questionnaire. Determining dietary quality across patient cohorts involved the use of 4 food-based scores, including an alternative Mediterranean diet score, an original plant-based diet index, a healthy plant-based diet index, and an unhealthy plant-based diet index.

Use of logistic generalized additive models determined whether a higher adherence to a specific diet correlated with a higher likelihood of response or IRAEs among patients.

The study included 44 patients from the PRIMM-NL trial and 47 patients in the PRIMM-UK trial. Most patients in each respective cohort had previously received single agent PD-L1 inhibition (73% vs 51%). Most patients in PRIMM-NL had stage M1d disease (39%), and most of those in PRIMM-UK had stage M1c disease (36%).

In terms of diet scores, the mean score was 3.07 (standard deviation [SD], 1.25) for alternative Mediterranean diets, 30.52 (SD, 4.29) for original plant-based diet index, 32.84 (SD, 5.81) for healthy plant-based diet index, and 31.70 (SD, 4.56) for unhealthy plant-based diet index in the PRIMM-NL population. For the PRIMM-UK population, the respective mean diet scores were 2.55 (SD, 1.28), 34.23 (SD, 4.45), 35.49 (7.37), and 34.32 (5.65), respectively.

For alternative Mediterranean diet scores, the log odds of being a responder increased by 1.43 for every unit increase in alternative Mediterranean diet score. Training on the PRIMM-UK cohort and validating on the PRIMM-NL cohort predicted PFS at 12 months and ORR by alternative Mediterranean diet scores with an area under the curve of 0.70.

In a principal component analysis, investigators noted a parabolic association of PC2 that was characterized by a high fruit intake with PFS at 12 months (P = .01; FDR, .018; edf, 2.14) and ORR (P = .01; FDR, .018; edf, 2.7) in the PRIMM-NL population. There were no significant associations observed within the PRIMM-UK population.

Individual components of the Mediterranean diet, including monounsaturated and polyunsaturated fatty acids, whole meal bread, vegetables, and legumes, as well as vitamins C and E and β-carotene were positively associated with response similar to alternative Mediterranean diet score. These associations, however, lacked statistical significance following multiple hypothesis testing corrections.

Investigators noted fewer IRAEs occurred with a diet high in legumes, whole-meal bread, and magnesium. Additionally, there were more IRAEs associated with higher processed meat intake.

Bolte suggested how a more widespread adoption of a Mediterranean diet may positively impact American patient populations while citing the need for additional research to affirm the health benefits observed in her study.

“The traditional principles of a Mediterranean diet are most recommended dietary principles by public health institutions globally. Unfortunately, a rising incidence of chronic diseases and cancer such as colorectal cancer, has been seen paralleling westernization of diets. We need larger studies across multiple geographies to further elucidate the role of diet in the context of cancer immunotherapy,” Bolte concluded.


Bolte LA, Lee KA, Björk JR, et al. Association of a Mediterranean diet with outcomes for patients treated with immune checkpoint blockade for advanced melanoma. JAMA Oncol. Published online February 16, 2023. doi:10.1001/jamaoncol.2022

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