Tumor-associated macrophages are strongly related to vascular invasion, non-luminal subtypes, and interval breast cancer

Abstract

Tumor-associated macrophages (TAM) resemble M2 macrophages, promote tumor invasion and show strong expression of CD163 in breast cancer. We here investigated the association between CD163-positive macrophages and vascular invasion, molecular subgroups, mode of detection, and patient outcome. We performed a population-based, retrospective study of invasive breast cancer from the Norwegian Breast Cancer Screening Programme in Vestfold County (2004-2009), including 200 screen-detected and 82 interval cancers. Immunohistochemically CD163-positive macrophages were counted in the most active areas (hotspots) and dichotomized as high (upper quartile) and low counts. Lymphatic vessel involvement (LVI) and blood vessel invasion (BVI) were recorded separately based on immunohistochemical staining (D2-40 and CD31 antibodies). High levels of CD163-positive macrophages were associated with BVI and lymphatic involvement as well as interval cancer detection when compared to screening-detected tumors. In addition, the presence of high CD163+ TAM levels was more often observed in HER2-positive, basal-like and Triple-negative breast cancers and was associated with several features of aggressive tumors. In survival analyses, cases with combined high CD163 counts and BVI showed a significantly reduced recurrence-free survival (RFS) and disease-specific survival (DSS) (P < .001 for both) compared with all other cases. The presence of CD163-positive, tumor-associated macrophages is strongly related to aggressive features of breast cancer such as vessel invasion, detection between screening intervals, non-luminal molecular subgroups and reduced survival.

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

“…Similarly, M2 infiltration in breast cancer was markedly correlated with larger tumor size, advanced stages, and angiogenesis. Polarization toward the M2 phenotype showed strong correlation with the aggressiveness of breast cancer characterized by higher histologic grade, higher Ki-67 proliferating index, estrogen receptor and progesterone receptor negativity (22,23).…”

Tumor-associated macrophages in breast cancer: Innocent bystander or important player?

“…High density of cells expressing macrophage-associated markers in primary breast cancer was associated in general with worse patient prognosis (Table 1) [23][24][25][26][27][28][29][30][31][32]. In general, included studies were of high Fig.…”

“…CD163 has been validated as marker for protumor M2-like macrophages [8,34]. CD163+ TAMs in primary breast cancers were strongly associated with adverse clinicopathological characteristics [20,25,26,29,30], and were independently prognostic for DFS, BCSS or OS in most studies [20,25,26,29,30] (Table 1). Similarly, the prognostic value of CD163+ macrophages may depend on breast cancer subtype.…”

The Complex Interaction between the Tumor Micro-Environment and Immune Checkpoints in Breast Cancer

“…M2 macrophages express arginase 1 (ARG1), anti-inflammatory cytokines, and proteases that support their pro-oncogenic functions [19]. Increased numbers of CD163+ M2 macrophages associate with unfavorable prognosis linked to non-luminal and basal-like breast cancer subtype [96,97]. In addition, vascular endothelial growth factor (VEGF) secretion by TAM stimulate tumor angiogenesis, promoting its invasiveness and metastatic potential [98,99,100].…”