Clever-1 positive macrophages in breast cancer

Abstract

Purpose Common Lymphatic Endothelial and Vascular Endothelial Receptor 1 (Clever-1) is expressed by a subset of immunosuppressive macrophages and targeting the receptor with therapeutic antibodies has been shown to activate T-cell-mediated anti-cancer immunity. The aim of this research was to study Clever-1 expression in breast cancer. Specifically, how Clever-1 + macrophages correlate with clinicopathologic factors, Tumor Infiltrating Lymphocytes (TILs) and prognosis. Methods Tissue microarray blocks were made from 373 primary breast cancer operation specimens. Hematoxylin and Eosin (H&E-staining) and immunohistochemical staining with Clever-1, CD3, CD4 and CD8 antibodies were performed. Differences in quantities of Clever-1 + macrophages and TILs were analyzed. Clever-1 + cell numbers were correlated with 25-year follow-up survival data and with breast cancer clinicopathologic parameters. Results Low numbers of intratumoral Clever-1 + cells were found to be an independent adverse prognostic sign. Increased numbers of Clever-1 + cells were found in high grade tumors and hormone receptor negative tumors. Tumors that had higher amounts of Clever-1 + cells also tended to have higher amounts of TILs. Conclusion The association of intratumoral Clever-1 + macrophages with better prognosis might stem from the function of Clever as a scavenger receptor that modulates tumor stroma. The association of Clever-1 + macrophages with high number of TILs and better prognosis indicates that immunosuppression by M2 macrophages is not necessarily dampening adaptive immune responses but instead keeping them in control to avoid excess inflammation.

Defining and targeting macrophage heterogeneity in the mammary gland and breast cancer

“…Intratumoral STAB1+ macrophage infiltration correlated with improved patient outcome and higher CD8+ T cell infiltration. However, no significant effects on patient outcome or immune cell infiltrate were correlated with STAB1+ macrophages localized to the peritumoral stroma 136 . This study contradicts current literature regarding reported STAB1+ macrophage functionality; thus, more studies are needed to understand this macrophage subset.…”

“…50,135 STAB1+ macrophages have additionally been found in samples from human breast cancer patients, and the effects of STAB+ expression on patient outcome were stratified based on localization within the tumor. 136 Intratumoral STAB1+ macrophage infiltration correlated with improved patient outcome and higher CD8+ T cell infiltration. However, no significant effects on patient outcome or immune cell infiltrate were correlated with STAB1+ macrophages localized to the peritumoral stroma.…”

“…STAB1+ macrophages have been functionally linked with phagocytic apoptotic clearance, an anti‐inflammatory, tumor‐supporting function in the TME 50,135 . STAB1+ macrophages have additionally been found in samples from human breast cancer patients, and the effects of STAB+ expression on patient outcome were stratified based on localization within the tumor 136 . Intratumoral STAB1+ macrophage infiltration correlated with improved patient outcome and higher CD8+ T cell infiltration.…”

Metabolic Barriers in Cancer and Cancer Therapy

“…These preclinical results led to a phase 1 trial to determine the safety and preliminary effectiveness of FP-1305, a humanized anti-Clever-1 antibody administered to heavily pretreated patients with metastatic solid tumors (269). Encouraging results of this trial indicated a proinflammatory switch of monocytes, enhanced capability of macrophages to cross-present scavenged antigens, and activation of T cells (270). TAMs also express PD-1, which inhibits phagocytosis and tumor immunity, impairing the PD-1/ PD-L1 axis in macrophages.…”

The cross-talk between macrophages and tumor cells as a target for cancer treatment

“…These preclinical results led to a phase 1 trial to determine the safety and preliminary effectiveness of FP-1305, a humanized anti-Clever-1 antibody administered to heavily pretreated patients with metastatic solid tumors ( 269 ). Encouraging results of this trial indicated a proinflammatory switch of monocytes, enhanced capability of macrophages to cross-present scavenged antigens, and activation of T cells ( 270 ). TAMs also express PD-1, which inhibits phagocytosis and tumor immunity, impairing the PD-1/PD-L1 axis in macrophages.…”