Gene Expression of the D-Series Resolvin Pathway Predicts Activation of Anti-Tumor Immunity and Clinical Outcomes in Head and Neck Cancer

Abstract

In human medicine, the progression from early neoplasia development to either complete resolution of tumorigenesis and associated inflammation or chronicity and fatal outcomes remain difficult to predict. Resolution of inflammation is an active process that stimulates the termination of the inflammatory response and promotes return to homeostasis, while failure in resolution contributes to the development of a number of diseases. To understand how resolution pathways contribute to tumorigenesis, we defined and employed a cumulative score based on the expression level of genes involved in synthesis, signaling, and metabolism of the D-series resolvin (RvD). This score was used for comparative analyses of clinical, cellular, and molecular features of tumors, based on RNA-sequencing (RNA-seq) datasets collected within The Cancer Genome Atlas (TCGA) program. Our results indicate that higher RvD scores are associated with better clinical outcome of patients with head and neck squamous cell carcinoma (HNSC), and with molecular and cellular signatures indicative of enhanced anti-tumor immunity and better response to immune-checkpoint inhibitors (ICI), also in human papilloma virus (HPV) negative HNSC subtypes. Thus, higher activity of the RvD pathway identifies patients with improved resolution and a more efficient immune reaction against cancer.

Is Lipid Metabolism of Value in Cancer Research and Treatment? Part II: Role of Specialized Pro-Resolving Mediators in Inflammation, Infections, and Cancer

“…RvD2, RvD3, and RvD4 have also been demonstrated to reduce metastases in tumor-bearing mice of lung, liver, and pancreatic cancers [52]. Notably, the gene expression of D-series-resolving biosynthetic enzymes is suggested to be a predictor with better clinical outcomes in patients with head and neck squamous cell carcinomas [193]. MaR1 reduced UVB-induced skin edema, neutrophil recruitment, cytokine production, matrix metalloproteinase-9 activity, keratinocyte apoptosis, epidermal thickening, mast cell count, and degradation of skin collagen in hairless mice [30].…”

Roles of Resolvins in Chronic Inflammatory Response

“…The application of the accumulative score relies on the gene expression related to the generation, metabolism, and signaling of D series resolvins to comparatively analyze the relationship between the resolution of inflammation and tumorigenesis. As a result, a higher RvD score distinguishes patients with an improved resolution of inflammation who can benefit from an anticancer treatment [ 141 ]. Regardless of the method of directly supplementing exogenous resolvins or increasing endogenous resolvins, resolvins have certain effects on the resolution of inflammation and the maintenance of homeostasis in vivo.…”

The Impact of Resolution of Inflammation on Tumor Microenvironment: Exploring New Ways to Control Cancer Progression

“…A high RvD score also associates to a signature suggestive of enhanced anti-tumor immunity, as demonstrated by its association to genes involved in the cytotoxic activity of immune cells (e.g., granzymes and perforin). Finally, a high RvD score is presumably linked to increased responsivity to immune-checkpoint inhibitors (ICI), as demonstrated by its significant correlation with the expression of four immune-checkpoint inhibitor targets (CD274, CTLA4, LAG3, and PDCD1) [ 62 ].…”