Considering the protumoral functions of TAMs new

Considering the protumoral functions of TAMs, new therapies against TAMs have recently gained interest. Such treatments, particularly inhibitors of the colony stimulating factor 1 receptor (CSF-1R), are currently evaluated in several clinical trials [19]. CSF-1R inhibitors may also be of interest in head and neck carcinoma (OSCC and other primary sites). In addition, reprogramming TAMs from M2 protumoral phenotype toward M1 antitumoral phenotype seems to be an interesting approach. Another area of research involves combinations with established treatment to enhance tumor response.
Discussion
Conclusion In OSCC, high density of TAMs is associated with a poor prognosis [15], [18]. However, the prognostic value was sparsely studied in other primary sites of head and neck carcinoma such as laryngeal and hypopharyngeal carcinomas. Using only the CD68 marker without a specific marker of M2 macrophages, one study analyzed the macrophages in laryngeal carcinoma [25]. It would be interesting to evaluate the occurrence of TAMs in laryngeal or hypopharyngeal subtypes and the correlation between the density of TAMs and survival parameters. Intriguingly, in colorectal cancer, high density of TAMs seems to be associated with a better OS in RSL3 to the majority of other solid tumors [15]. In addition, in the meta-analysis of Zhang et al., no significant correlation between high density of TAMs and tumor stage or OS was found in a subgroup of esophageal cancer patients [15]. Larynx and hypopharynx cancer belong to head and neck carcinoma, but they are not similar to OSCC, due to their localization and carcinogenesis [107], [108]. Thus, it would be interesting to know if the results concerning TAMs in larynx and hypopharynx cancer are comparable to those in OSCC. Moreover, in HPV-induced cervical cancer, the correlation between prognosis and the density of TAMs is unclear [109], [110]. Only two studies compared the incidence of CD68 + cells between HPV + and HPV- head and neck squamous cell carcinomas [39], [40]. These analyses were restricted to the CD68 status of tumors, therefore information on TAMs is lacking since no staining with CD163 was performed. Yu et al. did not find a correlation between CD68 or CD163 and HPV status [40]. However, a correlation between HPV status and macrophages was not the primary objective of their analysis. Hence, it would be interesting to further study the frequency of TAMs in HPV + and HPV- subgroups. The mutual interaction between TAMs and cancer cells plays a crucial role in tumor progression. Therefore, inhibitors of TAMs seem to be a viable target for future drug investigations. Different strategies are used to exploit TAMs as a therapeutic target in cancer [111]. Currently, the most promising approaches include inhibitors of the CSF-1/CSF-1R and SIRPα/CD47 pathways. The SIRPα/CD47 axis seems to be an interesting molecular cascade with several options being tested for targeting thereof [73], [74]. Moreover, the SIRPα/CD47 axis could be blocked by PD-1 inhibitors already used in clinical practice [40]. Recent clinical trials testing CSF-1R inhibitors used as single agent, unfortunately, showed disappointing outcomes in solid tumors. These unsatisfactory results of CSF-1R inhibitors were partly explained by the presence of GM-CSF inhibiting anti-CSF-1R-mediated cell death [69], [71]. Combining CSF-1R inhibitors with other compounds such as immunotherapy, chemotherapy, or targeted therapies could represent the next step to investigate [19]. Various imaging modalities can be used to visualize TAMs. The development of fluorescent proteins allows subcellular-resolution molecular imaging of cell-cell interactions between tumor cells and TAMs [112], [113]. In clinical practice, new imaging protocols revealing details on macrophage infiltration (e.g. ferumoxytol) can be considered in the future to observe TAMs activity by magnetic resonance or positron emission tomography [114], [115].