Prognostic Significance of Tumour-Associated Macrophages in Head and Neck Cancers: a Systematic Literature Review and a Study into their Effects in Nasopharyngeal Carcinoma

Abstract

Foreword: This bachelor thesis consists of two articles, a systematic literature review that assesses the diverse roles of macrophages in head and neck cancers and a scientific research article identifying the prognostic role of macrophages in nasopharyngeal carcinoma.

Article 1: Prognostic Significance of Tumour-Associated Macrophages in Cancers of the Head and Neck: a Systematic Literature Review BACKGROUND: Head and neck cancers account for a global incidence of more than 650,000 cases annually. Since head and neck cancers are characterized by poor survival rates it is essential to identify prognostic factors. Tumour-associated macrophages (TAMs) have a diverse set of functions in tumours and can be both pro- and anti-tumourogenic. OBJECTIVE: To assess the prognostic role of TAMs for survival in HNSCCs with a focus on identifying diverse roles of the subpopulations of TAM in a systematic literature review. METHODS: A systematic search of PubMed and Embase was performed for publications matching the domain of “head and neck cancer,” determinate of “macrophages” up to the date of 7th of July, 2016. All the articles were screened for prognostic studies that matched with the domain and the determinate. Using Quality in Prognostic Studies (QUIPS) relevant studies were evaluated for risk of bias. Information on immunomarkers, macrophage subtypes and other relevant clinicopathologic characterteristics was extracted from the data and compared. RESULTS: The initial search generated 281 studies. Eight studies were finally selected on the inclusion criterion. This included 6 studies focused on oral squamous cell carcinoma (OSCC), 1 study on oropharyngeal squamous cell carcinoma (OPSCC) and 1 study on supraglottic laryngeal carcinoma. All 8 studies looked at pan-macrophage marker CD68, while 3 studies looked at M2 macrophage-specific marker CD163. Four of the studies reported that elevated CD68 count was related to poor survival outcome, while the other four reported non-significant findings regarding CD68 association with survival. The 3 studies looking at CD163, all reported significant correlation with poor prognosis. CONCLUSIONS: Although some bias cannot be excluded, high density of TAM seems to be associated with worse overall survival in head and neck squamous cell carcinoma. M2 macrophage plays an active role in tumour development and progression.

Article 2: The Prognostic Significance of Tumour-Associated Macrophages in Nasopharyngeal Carcinoma BACKGROUND: Nasopharyngeal carcinoma (NPC) is characterized by considerable amount of immune infiltrate. There is controversy among studies about whether tumour-associated macrophages (TAMs) density positively or negatively affect prognosis in tumours. Since NPC differs so significantly from other cancers of the head and neck region it is imperative to identify suitable prognostic factors. OBJECTIVES: To assess the prognostic significance of TAMs and T regulatory cells (Tregs) in NPC. MATERIALS AND METHODS: This study included 92 patients with NPC. CD68, CD163 and FoxP3 antibodies were used to identify and assess the expression levels of TAMs and T regulatory cells using immunohistochemistry. A tissue microarray was used for the high throughput analysis of the samples. Samples were semi-quantitatively scored and divided into groups of high and low expression. Correlations between clinicopathologic characteristics were assessed using the Pearson X2 test and ANOVA for continues variables. Survival analyses were performed using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: The mean immunomarker counts of CD68 and FoxP3 were significantly higher in EBV positive cells compared to EBV negative cells and elevated CD68 and FoxP3 expression was correlated with EBV-positive NPCs. Both CD68 and CD163 were positively correlated with high FoxP3 expression. Elevated FoxP3 expression was strongly associated with increased overall survival (HR 3.283 (95% CI: 1.139-9.464)). Macrophage markers, CD68 andCD163, did not show significant relation to survival. CONCLUSIONS: Elevated levels of Tregs, immune cells that have previously been associated with tumour progression, are in fact beneficial for survival in patients with NPC. This may however be related to the EBV status in NPCs. Despite significant differences in TAM density in the different NPC subsets, neither macrophage marker was significantly correlated with survival rate.