Prognostic Significance of Tumor-Associated Macrophage Content in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) exists within a microenvironment rich in immune cells. Macrophages are particularly abundant in and around tumor tissue, and have been implicated in the growth, malignancy, and persistence of HNSCC ( 1 ). However, current literature reports variable degrees of association between the density of tumor-associated macrophages (TAMs) and clinicopathologic markers of disease ( 2 , 3 ). These inconsistent findings may be a result of differences in approach to TAM detection. Authors have measured total TAMs in tumor tissue, while others have stained tumor samples for individual subtypes of TAMs, which include pro-inflammatory (M1-like) and immunosuppressive (M2-like). Our aim is to more clearly define the prognostic significance of the phenotypes of tumor-associated macrophages in HNSCC. Methods: We conducted a meta-analysis of the existing publications investigating the relationship between TAMs (total and M2-like subtype) and T stage, nodal involvement, vascular invasion, lymphatic invasion, and tumor differentiation ( Figure 1 ). A total of 12 studies were included. Forest plots and risk ratios were generated to report overall effect. Results: Higher density of both total and M2-like subtype of TAMs in the tumor microenvironment is associated with advanced T stage, increased rates of nodal positivity, presence of vascular invasion, and presence of lymphatic invasion ( p < 0.0001; Figures 2–9 ). There is no significant association between TAM density, either total or M2-like subtype, and tumor differentiation ( Figures 10 , 11 ). Conclusions: Increased density of TAMs, including those of the M2-like phenotype, correlate with poor clinicopathologic markers in HNSCC. Our findings warrant additional investigation into the subpopulations of TAMs, the mechanisms behind their recruitment and differentiation, and the associated influence of each phenotype on tumor growth and invasion. A greater understanding of TAM dynamics in HNSCC is critical for directing further research and employing TAM-targeted adjunct therapies.

Infiltrates of M2-Like Tumour-Associated Macrophages Are Adverse Prognostic Factor in Patients with Human Papillomavirus-Negative but Not in Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma

“…As we know this is the first publication covering such a homogeneous group of patients with a comparable number of HPV-positive and HPV-negative cases and one of the few in which the HPV double-detection algorithm was used. Most of the publications in which the intensity of macrophage infiltration within head and neck tumours was analysed concerned locations in the oral cavity [30] or other locations outside the oropharynx [31], where HR-HPV status was unknown. Due to the low frequency of HR-HPV infections in the 2.5-4% range in these anatomical sites, it can be assumed that the results presented in them relate mainly to the HPV-negative population [32][33][34].…”

“…Subsequently, in all the examined cases, the presence and types of HR-HPV DNA in the tumour cells were confirmed using commercially available test, Sacace HPV Genotypes 14 Real-TM (Sacace Biotechnologies Srl, Italy), which is a real-time PCR Kit for quantitative detection and genotyping of HR-HPV (16,18,31,33,35,39,45, 51, 52, 56, 58, 59 and 68). The first step of the procedure was to isolate the genomic DNA from all tumour tissue samples by using Mag Core Genomic DNA FFPE One-step Kit and MagCore Nucleic Acids Automatic Extractor HF16-Plus (RBC Bioscience Corp. Taiwan).…”

Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice

“…Visual details on protein distribution and localization can be procured without the need to destroy the histologic architecture of a tissue (48). Accordingly, studies focusing on TAM characterization in solid clinical samples often adopt immunohistochemistry in their methodologies till date (8,49,50). In contrast, methods such as flow cytometry and gene expression are performed in vitro and could not reflect the complexity of immune responses observed in vivo (51,52).…”

A novel comprehensive immune-related gene signature as a promising survival predictor for head and neck squamous cell carcinoma

“…Our results show that the high level of Tregs infiltration is significantly associated with the low risk score, which is associated with favorable prognosis. Macrophages that infiltrate into the tumor microenvironment may facilitate tumor growth, angiogenesis, invasion, and metastasis, and are associated with poor prognosis in HNSCC [50]. Our study indicated that they are positively associated with risk score and an increase in M0 macrophages portends a poor prognosis.…”