Effect of Early-Stage Human Breast Carcinoma on Monocyte Programming.

Marina Patysheva,Christel Weiss,Pavel Iamshchikov,Militsa Rakina,Irina Larionova,Lilia Zhuikova,Julia Kardashova,Evgeniya Grigoryeva,Anastasia Frolova,Elizaveta Prostakishina,Nadezhda Cherdyntseva,Julia Kzhyshkowska,Marina Stakheyeva,Natalia Tarabanovskaya

doi:10.3389/fonc.2021.800235

Abstract

Circulating monocytes are a major source of tumor-associated macrophages (TAMs). TAMs in human breast cancer (BC) support primary tumor growth and metastasis. Neoadjuvant chemotherapy (NAC) is a commonly used treatment for BC patients. The absence of the response to NAC has major negative consequences for the patient: increase of tumor mass, delayed surgery, and unnecessary toxicity. We aimed to identify the effect of BC on the subpopulation content and transcriptome of circulating monocytes. We examined how monocyte phenotypes correlate with the response to NAC. The percentage of CD14-, CD16-, CD163-, and HLA-DR-expressing monocytes was quantified by flow cytometry for patients with T1-4N0-3M0 before NAC. The clinical efficacy of NAC was assessed by RECIST criteria of RECIST 1.1 and by the pathological complete response (pCR). The percentage of CD14+ and СD16+ monocytes did not differ between healthy women and BC patients and did not differ between NAC responders and non-responders. The percentage of CD163-expressing CD14lowCD16+ and CD14+CD16+ monocytes was increased in BC patients compared to healthy women (99.08% vs. 60.00%, p = 0.039, and 98.08% vs. 86.96%, p = 0.046, respectively). Quantitative immunohistology and confocal microscopy demonstrated that increased levels of CD163+ monocytes are recruited in the tumor after NAC. The percentage of CD14lowCD16+ in the total monocyte population positively correlated with the response to NAC assessed by pCR: 8.3% patients with pCR versus 2.5% without pCR (p = 0.018). Search for the specific monocyte surface markers correlating with NAC response evaluated by RECIST 1.1 revealed that patients with no response to NAC had a significantly lower amount of CD14lowCD16+HLA-DR+ cells compared to the patients with clinical response to NAC (55.12% vs. 84.62%, p = 0.005). NGS identified significant changes in the whole transcriptome of monocytes of BC patients. Regulators of inflammation and monocyte migration were upregulated, and genes responsible for the chromatin remodeling were suppressed in monocyte BC patients. In summary, our study demonstrated that presence of BC before distant metastasis is detectable, significantly effects on both monocyte phenotype and transcriptome. The most striking surface markers were CD163 for the presence of BC, and HLA-DR (CD14lowCD16+HLA-DR+) for the response to NAC.

Highlights

Breast cancer (BC) is the most common cancer among women and the second most common overall [1]
In this study for the first time, we have identified the monocyte biomarkers indicative for the presence of breast cancer and predicting the response of breast cancer patients to neoadjuvant chemotherapy, a broadly used approach to suppress the activity of primary tumor before the surgical intervention
We found the evidence that CD163 is elevated on the circulating monocytes in patients with breast cancer and is intensively recruited to the tumor site, suggesting that CD163 can be used as a marker for monocyte-derived tumor-associated macrophages (TAMs)

Summary

Introduction

Breast cancer (BC) is the most common cancer among women and the second most common overall [1]. The innate immune system controls primary tumor development, growth, angiogenesis, and metastatic spread [4]. Especially tumor-associated macrophages (TAMs), can both cooperate with chemotherapy and block its effects [5]. Circulating monocytes are precursors for the majority of TAMs that control tumor growth and metastasis [5–8]. Intratumoral microenvironments, including hypoxia, cancer cell-produced cytokines, and growth factors, promote both the recruitment of monocytes into tumor tissue and their differentiation toward tumor-supporting M2-like macrophages [9, 10]. Tumorassociated macrophages (TAM) are the most common and functionally active innate immune cells in the tumor microenvironment [6–9]. The differentiation of monocytes after their migration into tissues affects the TAM function and significantly affects intramural immune status, level of angiogenesis and lymphangiogenesis, proliferation of cancer cells, and efficiency of adaptive immune response [5, 13–15]. In majority of cancers, including breast, lung, prostate, and ovarian cancer, TAM substantially support tumor progression [12]

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