Study Explores Genomic and Transcriptomic Features of Anti–PD-1 Resistance in Advanced Melanoma
Immunotherapy using anti–programmed cell death 1 (PD-1) antibodies has revolutionized the treatment of advanced melanoma and a growing list of other cancers. But 60% to 70% of melanoma tumors are resistant to anti–PD-1 antibodies, and there is an urgent need to understand how to identify patients who will and will not respond to this therapy and ultimately improve response rates.
A new study by University of California, Los Angeles (UCLA) researchers has revealed how patterns of gene mutations and expression in a melanoma tumor before starting anti–PD-1 immunotherapy may predict whether the tumor will respond to therapy and if the treatment might produce survival benefits. Their findings were published by Hugo et al in Cell.
Roger Lo, MD, PhD, the study’s lead author and a UCLA Jonsson Comprehensive Cancer Center member, analyzed melanoma tumors from patients before anti–PD-1 therapy. The samples were subsequently divided into two groups, based on whether those patients responded or failed to respond to treatment. The researchers then sought to assess the “on” or “off” status of a tumor cell’s genes by detecting their mutational rates and/or gene-expression levels.
Key Results
“Once we observed how groups of genes were expressed at different levels between the responding vs nonresponding tumors, we could compute the biologic processes these genes likely participate in to promote resistance,” Dr. Lo said. “This anti–PD-1 resistance–associated gene-expression pattern defined a signature that was also detected across other common cancers of the lung, colon, kidney, and pancreas.”
The innately resistant tumors displayed a transcriptional signature (referred to as the IPRES, or innate anti–PD-1 resistance), indicating concurrent upregulation of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induced similar signatures in melanoma, suggesting that a nongenomic form of MAPK-inhibitor resistance mediates crossresistance to anti–PD-1 therapy.
From other computational experiments, the investigators also found that tumors with more mutations were associated with longer patient survival after anti–PD-1 therapy, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Additionally, researchers found another common therapy for advanced melanoma that utilizes small molecules to turn off a specific pathway activated by the BRAF mutation can induce processes inside a tumor similar to those associated with anti–PD-1 resistance.
Study Implications
Dr. Lo said the discovery suggests that, despite the potential of BRAF- and PD-1–targeted combination therapies to deliver further improvements in patient survival, future development of this approach should consider the altered immune microenvironment brought on by BRAF-targeted therapy.
The researchers hope the overall study findings have the potential to help explain why people battling the disease respond differently to or derive different degrees of long-term benefit from this type of treatment. Dr. Lo and his colleagues plan to begin validating significant associations discovered in this group of patients and designing predictive assays to help physicians stratify patients for PD-1 antibody therapy.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
