CD204‑positive macrophages accumulate in breast cancer tumors with high levels of infiltrating lymphocytes and programmed death ligand‑1 expression

Abstract

Although immunotherapy has been demonstrated to be promising in triple-negative (TN) breast cancer (BC), most BC cases are classified as non-TN. To enrich the responders for immunotherapy regardless of their subtypes, classification based on tumor-infiltrating lymphocyte (TIL) levels and programmed death ligand-1 (PD-L1) status may be useful. However, this classification has not been fully applied to BC. Furthermore, suppressive subsets in the local tumor microenvironment, such as tumor-associated macrophages (TAMs), which promote tumor progression, cannot be ignored to overcome immunotherapy resistance. The aims of the present study were to classify primary BC cases based on the TIL levels and PD-L1 status, and to identify suppressive immune subsets in each categorized group. A retrospective analysis of 73 patients with invasive BC was performed. The frequency of TILs was evaluated in HE-stained slides (10% cutoff), and PD-L1 levels (SP142; 1% cutoff), as well as immune subsets (CD3 + , CD8 + , FOXP3 + , CD20 + , CD68 + and CD204 + cells) were assessed using immunohistochemistry. It was revealed that 22% (16/73) of the tumors were categorized as TIL + PD-L1 + , of which 69% (11/16) were TN type. By contrast, 66% (48/73) of the tumors were categorized as TIL − PD-L1 − , of which 77% (37/48) were HR + and HER2 − types. The number of CD204 + M2-type macrophages was significantly associated with high histological grade (P=0.0246) and high Ki-67 (P=0.0152), whereas CD68 + macrophages were not associated with these factors. Furthermore, CD204 + macrophages and FOXP3 + Tregs accumulated in 88% (14/16) and 63% (10/16) of TIL + PD-L1 + tumors, respectively, compared with 20.8% (10/48) and 27.1% (13/48) of TIL − PD-L1 − tumors. In conclusion, 22% of BC tumors were classified as TIL + PD-L1 + (69% were TN), which were enriched with suppressive immune subsets. These cell types may serve as potential novel immunotherapeutic targets.

Multiplexed immunofluorescence identifies high stromal CD68+PD-L1+ macrophages as a predictor of improved survival in triple negative breast cancer

“…CD204, a Class A scavenger receptor associated with angiogenesis, immunosuppression and further tumour proliferation, is Vol:. ( 1234567890 www.nature.com/scientificreports/ another TAM marker used in studies investigating invasive breast cancer, with results again suggesting that high macrophage counts were also associated with poorer prognosis [59][60][61] . However, none have looked specifically at TNBC.…”

Hemangiosarcoma cells induce M2 polarization and PD-L1 expression in macrophages

“…In both ISOS-1 tumor and canine HSA cases, macrophages dominate the tumor parenchyma along with the tumor cells, thus, it is important to learn how these macrophages contribute to HSA pathogenesis. CD204 + macrophages in tumor tissues have been reported to express PD-L1, and they are associated with tumor malignancy and PD-L1 upregulation in tumor cells and immune cells 14 , 15 . We, therefore, examined PD-L1 expressions in tumor cells and macrophages in ISOS-1 tumors, clinical canine HSA cases and HSA cell lines.…”

“…M1 macrophages are polarized by lipopolysaccharides (LPS) and interferon-γ (IFNγ), while M2 macrophages are promoted by IL-4, IL-10 and TGFβ 11 – 13 . To distinguish M2 macrophages from M1 macrophages in tumor tissues, CD204 (also known as MSR1) has been used as a M2 macrophage marker 14 , 15 . Although LPS is an M1 macrophage inducer, LPS can also induce CD204 expression via the MAPK/ERK pathway in mouse macrophages 16 , 17 .…”

Hemangiosarcoma cells induce M2 polarization and PD-L1 expression in macrophages

“…In both ISOS-1 tumor and canine HSA cases, macrophages dominate the tumor parenchyma along with the tumor cells, thus, it is vital to know how these macrophages contribute to HSA pathology. CD204 + macrophages in tumor tissues have been reported to express PD-L1 and are associated with tumor malignancy and PD-L1 upregulation in tumor and immune cells 17,18 . Thus, we decided to examine PD-L1 expressions in tumor cells and macrophages in clinical HSA cases and HSA cell lines.…”