Cancer development and progression occurs in concert with alterations in the surrounding stroma. Cancer cells can functionally sculpt their microenvironment through the secretion of various cytokines, chemokines, and other factors. This results in a reprogramming of the surrounding cells, enabling them to play a determinative role in tumor survival and progression. Immune cells are important constituents of the tumor stroma and critically take part in this process. Growing evidence suggests that the innate immune cells (macrophages, neutrophils, dendritic cells, innate lymphoid cells, myeloid-derived suppressor cells, and natural killer cells) as well as adaptive immune cells (T cells and B cells) contribute to tumor progression when present in the tumor microenvironment (TME). Cross-talk between cancer cells and the proximal immune cells ultimately results in an environment that fosters tumor growth and metastasis. Understanding the nature of this dialog will allow for improved therapeutics that simultaneously target multiple components of the TME, increasing the likelihood of favorable patient outcomes.

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The Tumor Microenvironment Innately Modulates Cancer Progression

Infiltration of macrophages in solid tumours is associated with poor prognosis and correlates with chemotherapy resistance in most cancers. In mouse models of cancer, macrophages promote cancer initiation and malignant progression by stimulating angiogenesis, increasing tumour cell migration, invasion and intravasation and suppressing antitumour immunity. At metastatic sites, macrophages promote tumour cell extravasation, survival and subsequent growth. Each of these pro-tumoural activities is promoted by a subpopulation of macrophages that express canonical markers but have unique transcriptional profiles, which makes tumour-associated macrophages (TAMs) good targets for anticancer therapy in humans through either their ablation or their re-differentiation away from pro-tumoural towards antitumoural states. In this Review, we evaluate the state of the art of TAM-targeting strategies, focusing on the limitations and potential side effects of the different therapies such as toxicity, rebound effects and compensatory mechanisms. We provide an extensive overview of the different types of therapy used in the clinic and their limitations in light of known macrophage biology and propose new strategies for targeting TAMs.

Targeting macrophages: therapeutic approaches in cancer.

The international American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumour-node-metastasis (TNM) staging system provides the current guidelines for the classification of cancer. However, among patients within the same stage, the clinical outcome can be very different. More recently, a novel definition of cancer has emerged, implicating at all stages a complex and dynamic interaction between tumour cells and the immune system. This has enabled the definition of the immune contexture, representing the pre-existing immune parameters associated with patient survival. Even so, the role of distinct immune cell types in modulating cancer progression is increasingly emerging. An immune-based assay named the 'Immunoscore' was defined to quantify the in situ T cell infiltrate and was demonstrated to be superior to the AJCC/UICC TNM classification for patients with colorectal cancer. This Review provides a broad overview of the main immune parameters positively or negatively shaping cancer development, including the Immunoscore, and their prognostic and predictive value. The importance of the immune system in cancer control is demonstrated by the requirement for a pre-existing intratumour adaptive immune response for effective immunotherapies, such as checkpoint inhibitors. Finally, we discuss how the combination of multiple immune parameters, rather than individual ones, might increase prognostic and/or predictive power.

The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy.

Tumor-associated macrophages (TAMs) as immune cells within the tumor microenvironment have gained much interests as basic science regarding their roles in tumor progression unfolds. Better understanding of their polarization into pro-tumoral phenotype to promote tumor growth, tumor angiogenesis, immune evasion, and tumor metastasis has prompted various studies to investigate their clinical significance as a biomarker of predictive and prognostic value across different cancer types. Yet, the methodologies to investigate the polarization phenomena in solid tumor tissue vary. Nonetheless, quantifying the ratio of M1 to M2 TAMs has emerged to be a prevailing parameter to evaluate this polarization phenomena for clinical application. This mini-review focuses on recent studies exploring clinical significance of M1/M2 TAM ratio in human cancer tissue and critically evaluates the technicalities and challenges in quantifying this parameter for routine clinical practice. Immunohistochemistry appears to be the preferred methodology for M1/M2 TAM evaluation as it is readily available in clinical laboratories, albeit with certain limitations. Recommendations are made to standardize the quantification of TAMs for better transition into clinical practice and for better comparison among studies in various populations of patients and cancer types.

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Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice

It is generally accepted that metabolism is able to shape the immune response. Only recently we are gaining awareness that the metabolic crosstalk between different tumor compartments strongly cont...

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Immunity, Hypoxia, and Metabolism-the Ménage à Trois of Cancer: Implications for Immunotherapy.

// Xixi Zhao 1,* , Jingkun Qu 2,* , Yuchen Sun 3 , Jizhao Wang 2 , Xu Liu 2 , Feidi Wang 1 , Hong Zhang 1 , Wen Wang 1 , Xingcong Ma 1 , Xiaoyan Gao 1 and Shuqun Zhang 1 1 Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China 2 The Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China 3 The Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, P.R. China * These authors have contributed equally to this work Correspondence to: Shuqun Zhang, email: // Keywords : breast cancer, tumor associated macrophages, prognosis, meta-analysis Received : September 12, 2016 Accepted : February 06, 2017 Published : February 25, 2017 Abstract Purpose: Tumor associated macrophages (TAMs) are important prognostic factors and have been proved to be associated with the invasion and migration of various cancer. However, the relationship between TAMs and breast cancer outcomes remains unclear. Experimental Design: Sixteen studies with a total of 4,541 breast cancer patients were included in this meta-analysis. Correlation of TAMs with overall survival (OS), disease-free survival(DFS), relapse-free survival (RFS), breast cancer special survival (BCSS) and clinicopathological features were analyzed. Survival data and clinicopathological value were integrated by analyzing hazard ratio(HR) and odds ratio(OR) separately and using Fixed-effect or Random-effect model according to heterogeneity. All statistical tests were two-sided. Results: OS and DFS were correlated with high density of TAMs with HR= 1.504(1.200, 1.884)/ 2.228(1.716, 2.892) respectively. And subgroup analysis of location and biomarker in OS and DFS group showed prognosis was associated with TAMs distribution and biomarker selection. Besides, TAMs high infiltration was significantly related to age, size, histologic grade, ER/PR status, basal phenotype and vascular invasion. Conclusion: High density of TAMs was associated with poor survival rates of breast cancer. TAMs in stroma are associated with worse outcome than that in nest and using CD68 as a biomarker for TAMs to evaluate the risk is better than CD163 or CD206 alone. Moreover, high infiltration of TAMs was significantly associated with negative hormone receptor status and malignant phenotype. TAMs infiltration can serve as a novel prognostic factor in breast cancer patients.

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Prognostic significance of tumor-associated macrophages in breast cancer: a meta-analysis of the literature.

// Hong Zhang 1 , Yafei Zhang 2 , Wanjun Yan 1 , Wen Wang 1 , Xixi Zhao 1 , Xingcong Ma 1 , Xiaoyan Gao 1 , Shuqun Zhang 1 1 Department of Oncology, Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China 2 Department of General Surgery, Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China Correspondence to: Shuqun Zhang, email: 15229326653@163.com Keywords: breast cancer, rs3746444, rs11614913, rs2910164, meta-analysis Received: October 20, 2016      Accepted: November 12, 2016      Published: November 17, 2016 ABSTRACT Three functional microRNA polymorphisms (miR-499 rs3746444 A > G, miR-196a rs11614913 C > T and miR-146a rs2910164 G > C) have been reported to be associated with breast cancer (BC) risk. However, the results of the published studies are inconsistent. In order to obtain a more credible result, we conducted this meta-analysis. We searched PubMed, EMBASE and Web of Science databases to identify relevant studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association. Thirty-eight eligible studies with 17,417 cases and 18,988 controls were included in this meta-analysis. Our results showed that the rs3746444 was associated with an increased breast cancer risk in the four genetic models (G vs. A: OR = 1.17, P = 0.008; GG vs. AA: OR = 1.41, P < 0.001; AG vs. AA: OR = 1.10, P = 0.036; GG+AG vs. AA: OR = 1.16, P = 0.001). In the subgroup analysis by ethnicity, significant correlation remained in Asians but not in Caucasians. For rs11614913, obvious decreased breast cancer risk was observed in Caucasian populations (T vs. C: OR = 0.93, P = 0.044). However, we couldn't detect an association between rs2910164 and breast cancer risk. This meta-analysis demonstrates that rs3746444 could increase breast cancer risk in Asians and in general populations, while rs11614913 could decrease the risk of breast cancer in Caucasians. The rs2910164 polymorphism has no association with breast cancer risk. More multicenter studies with larger sample sizes are required to verify our results.

https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=13426&path%5B%5D=42595

Association between three functional microRNA polymorphisms (miR-499 rs3746444, miR-196a rs11614913 and miR-146a rs2910164) and breast cancer risk: a meta-analysis.

// Hong Zhang 1 , Yafei Zhang 2 , Xixi Zhao 1 , Xingcong Ma 1 , Wanjun Yan 1 , Wen Wang 1 , Zitong Zhao 1 , Qian Yang 1 , Xi Sun 3 , Hui Luan 4 , Xiaoyan Gao 1 and Shuqun Zhang 1 1 Department of Oncology, Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China 2 Department of General Surgery, Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China 3 Department of Integrated Traditional Chinese and Western Medicine, Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China 4 Department of Cardiology, First Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China Correspondence to: Shuqun Zhang, email: 15229326653@163.com Keywords: cancer, rs895819, rs6505162, meta-analysis Received: November 30, 2016     Accepted: February 27, 2017     Published: March 22, 2017 ABSTRACT Many studies have been conducted to investigate the association between miR-27 rs895819 A > G and miR-423 rs6505162 C > A and cancer risk; however, the results are not consistent. In order to acquire a more precise assessment of the correlation, we performed this meta-analysis. We searched PubMed, EMBASE and Web of Science databases to identify eligible studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the correlation of these two microRNA polymorphisms with cancer risk. Forty-five eligible studies from thirty-five articles were included in our analysis. The results showed that rs895819 was associated with a decreased cancer risk in Caucasians (AG vs. AA: OR = 0.87, 95% CI = 0.79-0.96; GG+AG vs. AA: OR = 0.89, 95% CI = 0.81-0.98). When grouped by ethnicity, an increased risk was observed in colorectal cancer (G vs. A: OR = 1.19, 95% CI = 1.08-1.32; GG vs. AA: OR = 1.58, 95% CI = 1.28-1.96; GG vs. AG+AA: OR = 1.58, 95% CI = 1.29-1.93), while a decreased risk was found in breast cancer (G vs. A: OR = 0.93, 95% CI = 0.87-0.99; GG+AG vs. AA: OR = 0.91, 95% CI = 0.83-0.99). For rs6505162, a significantly decreased cancer risk was observed in lung cancer under all five genetic models. To summarize, our results indicated that rs895819 was a protective factor for cancer in Caucasians and could increase colorectal cancer risk but decrease breast cancer risk. Moreover, rs6505162 was a protective factor for lung cancer.

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Association of two microRNA polymorphisms miR-27 rs895819 and miR-423 rs6505162 with the risk of cancer.

Subsequently to the publication of the above article, the authors have realized that the cell migration and tube formation assay data portrayed in Figs. 2 and 4 in their paper were published with some inadvertent errors. Specifically, the photograph selected for the ACHN-SFM group was accidentally misused for the 769P/LV-miR-218 group in Fig. 2F. Secondly, the photograph for the 786O/LV‑NC group in Fig. 2F was accidentally misused as the image for the 786O/shNC group in Fig. 4E; and thirdly, the photograph selected for the ACHN/shNC group in Fig. 4C was inadvertently misused for the ACHN/shNC group in Fig. 4D. These errors arose inadvertently as a consequence of the authors' mishandling their data; however, the authors were able to retrieve their original data, and have been able to reassemble these figures to show the data as was originally intended. The revised versions of Figs. 2 and 4, featuring the corrected data panels for the 769P/LV‑miR‑218 group in Fig. 2F, the ACHN/shNC group in Fig. 4D and the 786O/shNC group in Fig. 4E, are shown on the next two pages. The revised data shown for these Figures do not affect the overall conclusions reported in the paper. All the authors agree with the publication of this corrigendum. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [Oncology Reports 44: 1961‑1970, 2020; DOI: 10.3892/or.2020.7759].

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Wen Wang

Papers

Prognostic significance of tumor-associated macrophages in breast cancer: a meta-analysis of the literature.

Association between three functional microRNA polymorphisms (miR-499 rs3746444, miR-196a rs11614913 and miR-146a rs2910164) and breast cancer risk: a meta-analysis.

Association of two microRNA polymorphisms miR-27 rs895819 and miR-423 rs6505162 with the risk of cancer.

MicroRNA-218 inhibits tumor angiogenesis of human renal cell carcinoma by targeting GAB2