J Breast Cancer.  2019 Mar;22(1):38-51. 10.4048/jbc.2019.22.e5.

Tumor-Associated Macrophages as Potential Prognostic Biomarkers of Invasive Breast Cancer

• Jeong H
• Hwang I
• Kang SH
• Shin HC
• Kwon SY

• KMID: 2441850
• DOI: http://doi.org/10.4048/jbc.2019.22.e5

Abstract

PURPOSE
Tumor-associated macrophages (TAMs) are activated macrophages associated with tumor progression in various cancers. TAMs can polarize M1 or M2 type. M1 has a pro-inflammatory function and kills pathogens. Conversely, M2 shows immunosuppressive action and promotes tumor growth. There are various markers of TAMs. CD11c is considered as a specific marker of M1. CD163 is an optimal marker for M2. CD68 is known as a pan-macrophage marker. We evaluated the relationship between the clinicopathological parameters and immunohistochemical expressions of CD11c, CD163, and CD68 in invasive breast cancer (IBC), and the prognostic value of macrophage localization within the tumor stroma (TS) and tumor nest (TN).
METHODS
Immunohistochemistry of CD68, CD11c, and CD163 was analyzed on tissue microarrays of 367 IBCs. The number of CD68+, CD11c+, or CD163+ macrophages in TN vs. TS was counted by 2 pathologists. The correlations between the degree of macrophage (CD68+, CD11c+, or CD163+) infiltration and the clinicopathological parameters were analyzed. We also assessed the impact of macrophages (CD68+, CD11c+, or CD163+) on disease free survival (DFS) and overall survival (OS).
RESULTS
High numbers of macrophages (CD68+, CD11c+, or CD163+) were associated with higher histologic grade, higher Ki-67 proliferating index, estrogen receptor negativity, and progesterone receptor negativity. High numbers of macrophages (CD11c+ or CD163+) in TS were associated with a larger tumor size. Furthermore, CD163+ macrophages in TN were an independent prognostic marker of reduced OS and DFS. Conversely, CD11c+ macrophages in TS were an independent prognostic marker for higher OS and DFS.
CONCLUSION
TAMs, including M2 type, are associated with tumor progression in IBC. They can also act as a significant unfavorable or favorable prognostic factor. In addition to simply analyzing the degree of TAM infiltration, it is also important to analyze the location of TAMs.

Keyword

Breast neoplasms; CD11c antigen; CD163 antigen; CD68 antigen; Macrophages

MeSH Terms

Antigens, CD11c
Biomarkers*
Breast Neoplasms*
Breast*
Disease-Free Survival
Estrogens
Immunohistochemistry
Macrophages*
Receptors, Progesterone
Antigens, CD11c
Biomarkers
Estrogens
Receptors, Progesterone

Figure

• 

  Figure 1 Representative images of IHC analysis of TAM markers in IBC. (A) CD68+ macrophages are mostly present in TS (IHC for CD68, 400× magnification). (B) CD68+ macrophages are present in both TS and TN (IHC for CD68, 400× magnification). (C) CD11c+ macrophages are mainly present in TS (IHC for CD11c, 400× magnification). (D) CD11c+ macrophages are mostly present in TN (IHC for CD11c, 400× magnification). (E) CD163+ macrophages are chiefly present in TS (IHC for CD163, 400× magnification). (F) CD163+ macrophages are present in both TS and TN (IHC for CD163, 400× magnification). IBC = invasive breast cancer; IHC = immunohistochemistry; TAM = tumor-associated macrophage; TS = tumor stroma; TN = tumor nest.

• 

  Figure 2 Mean of the macrophages (CD68+, CD11c+, or CD163+) according to each molecular subtype. (A) CD68 in TS, (B) CD68 in TN, (C) CD11c in TS, (D) CD11c in TN, (E) CD163 in TS, and (F) CD163 in TN. HER2 = human epithelial growth factor receptor 2; TS = tumor stroma; TN = tumor nest. *p<0.05.

• 

  Figure 3 The OS curves according to the infiltration density of CD68+ macrophages in TS (A) and TN (B), CD11+ macrophages in TS (C) and TN (D), and CD163+ macrophages in TS (E) and TN (F) in IBC. OS = overall survival; TS = tumor stroma; TN = tumor nest; IBC = invasive breast cancer.

• 

  Figure 4 Disease free curves based on the infiltration density of CD68+ macrophages in TS (A) and TN (B), CD11+ macrophages in TS (C) and TN (D), and CD163+ macrophages in TS (E) and TN (F) in IBC. TS = tumor stroma; TN = tumor nest; IBC = invasive breast cancer.

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