Spatial distribution and prognostic value of tumor-associated macrophages in head and neck squamous cell carcinomas

Introduction Tumor-associated macrophages (TAMs) belong to the most frequent immune cells in the tumor microenvironment of head and neck squamous cell carcinomas (HNSCC). They can undergo an anti- or pro-tumoral polarization, the latter often referred to as M2-like activation. Because existing data are either not consistent, not well-connected to clinicopathological parameters or lack a detailed spatial distribution, we aimed to get more insight into the relevance of this immune cell population and their activation status. Methods This study analyzed the spatial distribution and prognostic value of CD68+TAMs and CD68+CD163+M2-like TAMs in different tumor compartments and tumor-distant stromal areas, in 85 treatment-naïve HNSCC. Various clinicopathological features were considered, such as major tumor sites, stage, T-stage, nodal status and p16-status. TAM and M2-like TAM densities were analyzed using multicolor immunofluorescence stainings followed by an objective tissue cytometry-based quantification at the single-cell level in whole tissue sections and subsequent uni- and multivariate survival analyses. Results Whereas we observed higher TAM and M2-like TAM densities in p16-negative HNSCC specimens, densities of M2-like TAMs were highest in the tumor-near stroma of advanced nodal-positive p16-negative HNSCC compared to tumor cell nests and tumor-distant stroma, particularly in younger and male patients and patients with hypopharynx carcinomas. Moreover, higher infiltration of M2-like TAMs turned out to be an independent prognostic factor of poorer survival even exceeding the impact of the p16-status and the tumor site. Discussion In summary, our data provide a strong rationale to target M2-like TAMs to improve success of immune-modulatory treatments and survival of patients suffering from p16-negative HNSCC.