Search

Macrophages are the most abundant immune cells of the tumor microenvironment (TME) and have multiple important functions in cancer. During tumor growth, both tissue-resident macrophages and newly recruited monocyte-derived macrophages can give rise to tumor-associated macrophages (TAMs), which have been associated with poor prognosis in most cancers. Compelling evidence indicate that the high degree of plasticity of macrophages and their ability to self-renew majorly impact tumor progression and resistance to therapy. In addition, the microenvironmental factors largely affect the metabolism of macrophages and may have a major influence on TAMs proliferation and subsets functions. Thus, understanding the signaling pathways regulating TAMs self-renewal capacity may help to identify promising targets for the development of novel anticancer agents. In this review, we focus on the environmental factors that promote the capacity of macrophages to self-renew and the molecular mechanisms that govern TAMs proliferation. We also highlight the impact of tumor-derived factors on macrophages metabolism and how distinct metabolic pathways affect macrophage self-renewal.

Oral cavity squamous cell carcinoma (OSCC) is a common head and neck cancer characterized by a poor prognosis associated with locoregional or distant failure. Among the predictors of prognosis, a dense infiltration of adaptive immune cells is protective and associated with improved clinical outcomes. However, few tools are available to integrate immune contexture variables into clinical settings. By using digital microscopy analysis of a large retrospective OSCC cohort (n = 182), we explored the clinical significance of tumor-infiltrating CD8+ T-cells. To this end, CD8+ T-cells counts were combined with well-established clinical variables and peripheral blood immune cell parameters. Through variable clustering, five metavariables (MV) were obtained and included descriptors of nodal (NODALMV) and primary tumor (TUMORMV) involvement, the frequency of myeloid (MYELOIDMV) or lymphoid (LYMPHOIDMV) peripheral blood immune cell populations, and the density of tumor-infiltrating CD8+ T-cells (TI-CD8MV). The clinical relevance of the MV was evaluated in the multivariable survival models. The NODALMV was significantly associated with all tested outcomes (p < 0.001), the LYMPHOIDMV showed a significant association with the overall, disease-specific and distant recurrence-free survival (p < 0.05) and the MYELOIDMV with the locoregional control only (p < 0.001). Finally, TI-CD8MV was associated with distant recurrence-free survival (p = 0.029). Notably, the performance in terms of survival prediction of the combined effect of NODALMV and immune metavariables (LYMPHOIDMV, MYELOIDMV and TI-CD8MV) was superior to the TNM stage for most of the outcomes analyzed. These findings indicate that the analysis of the baseline host immune features are promising tools to complement clinical features, in stratifying the risk of recurrences.