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      Comment on: Kadomoto, S. et al. “Tumor-Associated Macrophages Induce Migration of Renal Cell Carcinoma Cells via Activation of the CCL20-CCR6 Axis” Cancers 2020, 12, 89

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          Abstract

          Macrophages form a major component of the leukocyte infiltrate in solid tumors and it has become increasingly clear that tumor-associated macrophages (TAMs) have tumor-promoting effects within the stroma [1]. Renal cell carcinoma (RCC) solid tumors are comprised of a heterogeneous microenvironment of both malignant and normal stromal cells containing large numbers of macrophages [2]. We read with interest the paper by Suguru Kadomoto et al. entitled “Tumor-associated macrophages induce migration of renal cell carcinoma cells via activation of the CCL20-CCR6 axis”, published in Cancers [3], in which they report that the CCL20-CCR6 axis induces migration and epithelial–mesenchymal transition (EMT) of ACHN and Caki-1 RCC cells in co-cultures with THP-1/U937-derived tumor conditioned macrophages. We would like to widen the focus of the paper and make some additional comments. Importantly, we would like to point out the unclear macrophage polarization status of the phorbol 12-myristate 13-acetate (PMA)-treated cells used in the study, which the authors addressed in the discussion. The study is based on co-culture data from PMA-stimulated monocytic THP-1 and U937 cells that result in macrophage-like cells, probably lacking a specific M1 or M2 phenotype. Unfortunately, the resulting macrophage phenotype is insufficiently characterized by the authors thereby limiting the significance of the findings. In order to improve the informative value of this study, it would be useful to perform an additional M1-polarization of PMA-treated cells by interferon IFN-γ and toll-like receptor (TLR) ligand lipopolysaccharide (LPS) treatment, which leads to the secretion of high amounts of proinflammatory cytokines [4]. In addition, activation of a M2 phenotype by factors such as IL4, IL13, IL10 and colony stimulating factor 1 (CSF1) was not performed. Such treatments should lead to low production of proinflammatory cytokines, high production of the anti-inflammatory cytokines IL10 and cyclooxygenase-2 (COX-2) derived prostaglandin E2 (PGE2) as well as high expression of mannose (CD206) and scavenger (CD163) receptors [4]. Without clear profiling of the potential macrophage phenotypes present in the co-culture setting with a set of M1, M2 and TAM markers, the data do not support the conclusions presented. Importantly, TAMs do not fit entirely into the criteria for M1 or M2 macrophages [5] and patient data suggest that TAMs in RCC show a mixed M1/M2 phenotype [6]. Of interest, TAMs expressing high amounts of T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3), which is not a classical M1 or M2 marker, were associated with poor prognosis in clear cell RCC [7]. Moreover, the specific tumor microenvironment promotes differentiation of macrophages to heterogenous pro-tumoral TAM phenotypes in the same tumor [1]. Thus, we believe that PMA-treated THP-1 and U937 cells poorly reflect the situation in patient tumors. In future studies, the use of patient-derived TAMs from RCC cancer patients would be an alternative approach to address the role of TAMs in RCC in an in vitro setting. To support their findings, the authors performed immunohistochemical staining of CCR6 and CD68 in 42 RCC tissue samples and reported no association between CCR6 and CD68 positive tissues. CCL20 staining was not performed which would be necessary to identify potential overlap and correlation of TAM and CCL20 tissue distribution. In addition, the data do not address the question of whether TAMs are the major stromal source of CCL20 in RCC patients, which could be examined by isolating cancer cells, macrophages, infiltrating leukocytes and cancer associated fibroblasts from patients followed by measurement of CCL20 secretion in the cultures. Consequently, the co-culture data reported in this study are not supported by patient data. It would also be better to stain patient tissues with M1 and M2 markers in addition to the general macrophage marker CD68. In line with this suggestion, a previous study analyzed the presence of M1 and M2 macrophages in 185 RCC patients using histological techniques [6]. Using CD68 as a pan-macrophage marker, CD11c for M1 and CD206 as a M2-marker revealed that CD68 alone has a poor predictive value, whereas low CD11c and high CD206 expression as single variables correlated with reduced survival, whereas patients with high CD11c and low CD206 expression had the best survival prognosis [6]. In this context, it should be noted that CD68 was not needed in this analysis. In light of these findings, it is not surprising that CD68 staining did not result in any additional useful knowledge in the present study and underlines the necessity of a complex analysis, using markers for M1, M2 and TAM phenotypes. Given the important role of TAMs in the progression of RCC and the reported overexpression of CCR6 by cancer cells and aberrant signaling by its ligand CCL20 in many cancer types including colorectal, pancreatic and melanoma solid tumors [8,9,10,11] as well as the development of anti-cancer therapeutics inhibiting CCR6-CCL20 activity [12], investigation of the involvement and mechanisms of the CCL20-CCR6 axis contributing to the development and progression of renal cell cancer is a worthwhile undertaking.

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          Most cited references 6

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          Prognostic value of diametrically polarized tumor-associated macrophages in renal cell carcinoma.

          As the most abundant tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) are significant for fostering tumor progression. CD68(+) TAMs display diversely polarized programs comprising CD11c(+) proinflammatory macrophages (M1) and CD206(+) immunosuppressive macrophages (M2). The aim of this study was to determine the survival impact of diametrically polarized TAMs in clear-cell renal cell carcinoma (ccRCC) and their application to stratification of patients according to their prognostic values. The study included 185 consecutive patients with ccRCC who underwent nephrectomy between 1999 and 2001. CD68(+) total and diametrically polarized (CD11c(+) M1 and CD206(+) M2) TAM densities were assessed by immunohistochemistry, and the relationships with clinicopathologic features and prognosis were evaluated. Low CD11c(+) TAM density and high CD206(+) TAM density were associated with reduced cancer-specific survival (P = 0.043 and P = 0.017, respectively), whereas CD68(+) TAM density only had borderline prognostic significance (P = 0.062). Furthermore, combined analysis of CD11c(+) and CD206(+) TAMs (CD11c/CD206 signature) had a better power to predict patients' outcome (P = 0.010). Together with TNM stage, tumor necrosis, and performance status, CD11c/CD206 signature was an independent prognostic factor (P = 0.010). When applied to the University of California Integrated Staging System intermediate-/high-risk group for localized ccRCC, CD11c/CD206 signature could further distinguish patients with dismal prognosis (P = 0.004). Intratumoral balance of diametrically polarized TAMs is a novel independent predictor for survival in patients with ccRCC. Tipping the balance toward an antitumoral phenotype might be a promising target of postoperative adjuvant therapy.
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            The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas.

            Clear cell renal cell carcinoma (ccRCC) is one of most common cancers in urogenital organs. Although recent experimental and clinical studies have shown the immunogenic properties of ccRCC as illustrated by the clinical sensitivities to various immunotherapies, the detailed immunoregulatory machineries governing the tumorigenicity of human ccRCC remain largely obscure. In this study, we demonstrated the clinical significance and functional relevance of T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) expressed on tumor cells and myeloid cells in patients with ccRCC. TIM-3 expression was detected on cancer cells and CD204(+) tumor-associated macrophages (TAM), and higher expression level of TIM-3 was positively correlated with shorter progression-free survival (PFS) in patients with ccRCC. We found that TIM-3 expression was detected on a large number of tumors, and there was significant correlation between an increased number of TAMs and high expression level of TIM-3 in patients with ccRCC. Furthermore, TIM-3 rendered RCC cells with the ability to induce resistance to sunitinib and mTOR inhibitors, the standard regimen for patients with ccRCC, as well as stem cell activities. TIM-3 expression was induced on CD14(+) monocytes upon long-term stimulation with RCC cells, and TIM-3-expressing myeloid cells play a critical role in augmenting tumorigenic activities of TIM-3-negative RCC cells. More importantly, treatment with anti-TIM-3 mAb suppressed its tumorigenic effects in in vitro and in vivo settings. These findings indicate the coordinated action of TIM-3 in cancer cells and in myeloid cells regulates the tumorigenicity of human RCC.
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              Detection and localization of Mip-3alpha/LARC/Exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer.

              Macrophage Proinflammatory Human Chemokine-3alpha (Mip-3alpha/LARC/Exodus) belongs to a large family of chemotactic cytokines, which participate in directing inflammatory cell migration and in modulating angiogenesis. Mip-3alpha signals through a recently identified G-protein linked 7-transmembrane receptor, CCR6. In this study, we have characterized the expression of Mip-3alpha and CCR6 in 12 normal and 16 cancerous human pancreatic tissues and in 4 cultured pancreatic cancer cell lines, and assessed the effects of Mip-3alpha on growth and invasion of these cell lines. Pancreatic cancer tissues markedly overexpressed Mip-3alpha in comparison with normal pancreatic samples. By in situ hybridization Mip-3alpha and CCR6 mRNA moieties were present in cancer cells within the tumors. In addition, Mip-3alpha was abundant in the macrophages infiltrating the tumor mass. Mip-3alpha and its receptor CCR6 were expressed in all 4 tested pancreatic cancer cell lines. Mip-3alpha stimulated the growth of one cell line, enhanced the migration of another cell line, and was without effect in the other 2 cell lines. Together, our findings suggest that Mip-3alpha has the potential to act via autocrine and paracrine mechanisms to contribute to the pathobiology of human pancreatic cancer.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                03 February 2020
                February 2020
                : 12
                : 2
                Affiliations
                Center for Anatomy and Cell Biology, Division of Cell and Developmental Biology, Medical University of Vienna, Vienna 1090, Austria; karin.zins@ 123456meduniwien.ac.at
                Author notes
                [* ]Correspondence: dietmar.abraham@ 123456meduniwien.ac.at ; Tel.: +43-1-40160-37527
                Article
                cancers-12-00342
                10.3390/cancers12020342
                7072274
                32028699
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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