Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancers and is not eligible for hormone and anti-HER2 therapies. Identifying therapeutic targets and associated biomarkers in TNBC is a clinical challenge to improve patients’ outcome and management. High infiltration of CD206+ M2-like macrophages in the tumor microenvironment (TME) indicates poor prognosis and survival in TNBC patients. As we previously showed that membrane expression of GRP94, an endoplasmic reticulum chaperone, was associated with the anti-inflammatory profile of human PBMC-derived M2 macrophages, we hypothesized that intra-tumoral CD206+ M2 macrophages expressing GRP94 may represent innovative targets in TNBC for theranostic purposes. We demonstrate in a preclinical model of 4T1 breast tumor-bearing BALB/c mice that (i) CD206-expressing M2-like macrophages in the TME of TNBC can be specifically detected and quantified using in vivo SPECT imaging with 99mTc-Tilmanocept, and (ii) the inhibition of GRP94 with the chemical inhibitor PU-WS13 induces a decrease in CD206-expressing M2-like macrophages in TME. This result correlated with reduced tumor growth and collagen content, as well as an increase in CD8+ cells in the TME. 99mTc-Tilmanocept SPECT imaging might represent an innovative non-invasive strategy to quantify CD206+ tumor-associated macrophages as a biomarker of anti-GRP94 therapy efficacy and TNBC tumor aggressiveness.
Highlights
Breast cancer is one of the leading causes of death in women in developed countries.Triple-negative breast cancer (TNBC) represents 15–20% of all breast carcinomas [1]
GRP94 Is Co-Expressed by CD206+ M2-like Macrophages in Murine 4T1 and Human TNBC
We analyzed human TNBC biopsies and showed that some tumors were infiltrated with CD206+ M2-like macrophages co-expressing GRP94 (Figure 1B) whereas other tumors were not (Figure 1C)
Summary
Breast cancer is one of the leading causes of death in women in developed countries.Triple-negative breast cancer (TNBC) represents 15–20% of all breast carcinomas [1]. TNBC is defined by the absence of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [1]. It is the most aggressive subtype of breast cancers coupled with the highest probability of metastasis [2]. The identification of therapeutic targets in the tumor microenvironment (TME) of TNBC and associated biomarkers for molecular imaging is a clinical challenge, which may improve patients’ outcome and management. Infiltration of M2-like macrophages in the TME is associated with poor prognosis and survival in TNBC patients [4,5]. M2like macrophages play an essential role in tumor progression by stimulating angiogenesis, tumor cell invasion, and metastasis, and suppressing anti-tumor immunity [6,7,8]
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