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Why Do Some Patients With Melanoma Fail to Respond to Immunotherapy?

By: Cordi Craig
Posted: Monday, October 21, 2019

To evaluate why many patients with melanoma do not respond to immunotherapy, researchers investigated the mechanisms of response and found an association between the melanoma metabolic state and the response to immunotherapy. The results, published in Cell, suggest that lipid metabolism may be a regulatory mechanism that increases melanoma immune responses.

“In our research, we focused on metastatic melanoma, a devastating disease that until recently had no efficient treatments. It was clear to us that pretreatment samples from responders and nonresponders would be key,” corresponding author Gal Markel, MD, PhD, of Tel Aviv University, Israel, stated in an institutional press release.

The authors profiled the proteome of clinical samples from 116 patients with advanced-stage melanoma receiving either tumor-infiltrating lymphocyte-based or anti–PD-1 immunotherapy. Using high-resolution mass spectrometry, the authors quantified more than 10,300 proteins overall and approximately 4,500 proteins across most samples in each data set.

A comparison of proteomics of responders and nonresponders revealed major differences. The researchers found higher oxidative phosphorylation and lipid metabolism in patients who responded than in those who did not respond to both treatments. To determine the relationship between the metabolic state and immune responses, the authors examined melanoma cells upon CRISPR-Cas9 knockout mice. The experiments revealed that lipid metabolism appears to increase melanoma immunogenicity by elevating antigen presentation and increasing sensitivity to T-cell–mediated killing both in vitro and in vivo.

“In our study, we identified a significant difference between melanoma patients who live for years thanks to immunotherapy and patients who are not at all affected by the treatment,” stated study coauthor Tamar Geiger, PhD, also of Tel Aviv University. “Now, in subsequent studies, we are looking for ways to improve the response to immunotherapy and expand the circle of patients who benefit from it.”

Disclosure: Full disclosures for study authors can be found at cell.com.



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