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| Tissue biomarkers | T-lymphocytic and macrophages infiltrate |
| Human breast cancer | Canine mammary tumors |
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| Angiogenesis | (i) T-cells can secret VEGF [39]
(ii) Treg cells release TGFβ1 and induce VEGF expression [40]
(iii) M2 macrophages are responsible for the production of VEGF, uPA, MMP9, and CCL18 promoting tumor neovascularization [48, 51] | (i) Positive correlation between CD3+ T-cells, VEGF, and microvessel density [52]
(ii) M2 macrophages infiltration is associated with VEGF expression [56] |
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| Invasion and metastasis | (i) IL-10 produced by Th2-polarized CD4+ T-lymphocytes promotes M2-TAMs polarization, enhancing metastasis through EGFR signaling activation [60]
(ii) IL-1β elicits IL-17 expression from T-cells, resulting in expansion and polarization of neutrophils that have the ability to suppress cytotoxic CD8+ T-lymphocytes and favors metastatic spread [61]
(iii) MMP-2, MMP-9, and CCL18 produced by macrophages increase tumor cells motility and invasiveness [62, 63] | (i) CD4+ T-cells count and TAMs density are higher in metastatic CMT; CD8+ T-cells count is higher in tumors without metastatic behavior [64–66] |
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| COX-2 | (i) COX-2-derived PGE2 enhances the production of IL-4, IL-5, and IL-10 by Th2 cells and inhibits the antitumor Th1 cytokines (IFN-γ and IL-2) [67, 68]
(ii) PGE2 inhibits CD8+ T-cells proliferation and antitumor activities [69]
(iii) COX-2/PGE2 pathways increase tumor Treg cells infiltration, differentiation, and function [70] and can change the tumor-associated macrophages phenotype from M1 to M2 [71, 72] | (i) Tumors with high COX-2/CD3 and high COX-2/MAC are associated with tumor aggressiveness and shorter OS [73] |
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| Receptor tyrosine kinases | (i) T-lymphocytes and TAMs produce EGFR ligands being involved in tumor progression [74–76]
(ii) FoxP3+ Treg cells express EGFR under inflammatory conditions, which is related to tumor cells invasion and metastasis [77]
(iii) c-kit dependent signaling supports an immune twisting toward Th2 and Th17 subsets and the cytokines produced induce T-cell tolerance, contributing to cancer development [78–80]
(iv) c-kit inhibitors induce a reduction of TAMs and Treg cell numbers and contribute to the enhancement of Th1 and CD8+ T-cells [81–84] | (i) Concurrent COX-2/EGFR expression is associated with higher numbers of tumoral CD3+ T-lymphocytes and characteristics of tumor aggressiveness [19]
(ii) High CD3/c-kit tumors are associated with variables of tumor aggressiveness and shorter overall survival of animals [52] |
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