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Simple Summary: Melanoma is an immunogenic tumor, so its outcomes and the efficacy of immunotherapy must be linked to the immune component. In this study, we aimed to find indicators that would allow us to monitor both the prognosis of patients and the efficacy of immunotherapy. We found that complement C2 tended to be upregulated in patients after effective anti-PD-1 therapy, and the high expression group achieved longer survival. Tumor tissues with C2 expression were infiltrated with more M1-type macrophages and tertiary lymphoid structures, and this favorable immune status may be responsible for the favorable outcome. Our findings provide valuable insights into the functional role of C2 in melanoma and its potential implications for clinical therapy. Immunotherapy is an essential therapy for individuals with advanced melanoma. However, not all patients respond to such treatment due to individual differences. We conducted a multidimensional analysis using transcriptome data from our center, as well as publicly available databases. We found that effective nivolumab treatment led to an upregulation of C2 levels, and higher levels following treatment are indicative of a good outcome. Through bioinformatics analyses and immunofluorescence, we identified a correlation between C2 and M1 macrophages. To further investigate the role of C2 in melanoma, we constructed subcutaneous tumorigenic models in C57BL/6 mice. The tumors in the C2 overexpression group exhibited significantly smaller sizes. Flow cytometric analysis of the mouse tumors demonstrated enhanced recruitment of macrophages, particularly of the M1 subtype, in the overexpression group. Moreover, single-cell RNA sequencing analysis revealed that C2-positive tumor cells exhibited enhanced communication with immune cells. We co-cultured tumor cell supernatants with macrophages in vitro and observed the induction of M1 subtype polarization. In addition, we discovered a close correlation between C2 and tertiary lymphoid structures. C2 has been demonstrated to exert a protective effect, mediated by its ability to modulate the tumor microenvironment. C2 serves as a prognostic marker for melanoma and can be employed to monitor the efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) constitutes a complex microenvironment comprising a diverse array of immune cells and stromal components. Within this intricate context, tumor-associated macrophages (TAMs) exhibit notable spatial heterogeneity. This heterogeneity contributes to various facets of tumor behavior, including immune response modulation, angiogenesis, tissue remodeling, and metastatic potential. This review summarizes the spatial distribution of macrophages in both the physiological environment and the TME. Moreover, this paper explores the intricate interactions between TAMs and diverse immune cell populations (T cells, dendritic cells, neutrophils, natural killer cells, and other immune cells) within the TME. These bidirectional exchanges form a complex network of immune interactions that influence tumor immune surveillance and evasion strategies. Investigating TAM heterogeneity and its intricate interactions with different immune cell populations offers potential avenues for therapeutic interventions. Additionally, this paper discusses therapeutic strategies targeting macrophages, aiming to uncover novel approaches for immunotherapy. EjPgUqH7NocL1u9xj7Aojm Video Abstract [ABSTRACT FROM AUTHOR]

One-carbon (1C) metabolism, central carbon metabolism, and epigenetic modifications are dynamically altered in macrophages under stimulation. Metabolites of carbon metabolism could modify signaling pathways in macrophages to respond in a timely manner to external stimuli through epigenetic modification. Amino acids and mammalian target of rapamycin signaling regulate epigenetic modification in macrophages via 1C metabolism. Tumor cells shape carbon metabolism in the tumor microenvironment to orchestrate the epigenetic modification of tumor-associated macrophages. Carbon metabolism, including one-carbon (1C) metabolism and central carbon metabolism (CCM), provides energy for the cell and generates metabolites with signaling activities. The regulation of macrophage polarization involves complex signals and includes an epigenetic level. Epigenetic modifications through changes in carbon metabolism allow macrophages to respond in a timely manner to their environment and adapt to metabolic demands during macrophage polarization. Here we summarize the current understanding of the crosstalk between carbon metabolism and epigenetic modifications in macrophages under physiological conditions and in the tumor microenvironment (TME) and provide targets and further directions for macrophage-associated diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: The bodily response to cancer treatment is difficult to track in real time. This study aimed to demonstrate the possible application of magnetic resonance imaging (MRI) as a non-invasive and non-radiative modality to evaluate cancer response to therapy. We injected a fluorinated contrast agent in mouse models of breast and colon cancer to tag and track macrophages in real time. Longitudinal tracking of macrophages in tumors following radiation therapy via MRI provided a means of analyzing the tumor microenvironment without the need for a biopsy. It was shown that tumor-associated macrophage recruitment can be quantified through magnetic resonance imaging. Moreover, the findings suggest that macrophage response to radiation therapy is dependent on several factors including tumor origin. Since tumor recurrence following therapy is a major barrier following treatment, this imaging technique will be extremely beneficial in the future analysis of inflammation's role in that process. Background: Magnetic resonance imaging (MRI) is a non-invasive imaging modality which, in conjunction with biopsies, provide a qualitative assessment of tumor response to treatment. Intravenous injection of contrast agents such as fluorine (19F) nanoemulsions labels systemic macrophages, which can, then, be tracked in real time with MRI. This method can provide quantifiable insights into the behavior of tumor-associated macrophages (TAMs) in the tumor microenvironment and macrophage recruitment during therapy. Methods: Female mice received mammary fat pad injections of murine breast or colon cancer cell lines. The mice then received an intravenous 19F nanoemulsion injection, followed by a baseline 19F MRI. For each cancer model, half of the mice then received 8 Gy of localized radiation therapy (RT), while others remained untreated. The mice were monitored for two weeks for tumor growth and 9F signal using MRI. Results: Across both cohorts, the RT-treated groups presented significant tumor growth reduction or arrest, contrary to the untreated groups. Similarly, the fluorine signal in treated groups increased significantly as early as four days post therapy. The fluorine signal change correlated to tumor volumes irrespective of time. Conclusion: These results demonstrate the potential of 19F MRI to non-invasively track macrophages during radiation therapy and its prognostic value with regard to tumor growth. [ABSTRACT FROM AUTHOR]

Immunotherapies that target programmed cell death protein 1 (PD-1) signals are standard therapies for advanced-stage lung cancer, and the expression of programmed death-ligand 1 (PD-L1) in cancer tissue predicts immunotherapy efficacy. Although programmed death-ligand 2 (PD-L2) is expressed in cancer cells and macrophages, similar to PD-L1, its significance in lung cancer is unclear. Double immunohistochemistry analyses using anti-PD-L2 and anti-PU.1 antibodies were carried out on tissue array sections from 231 cases of lung adenocarcinoma, and PD-L2 expression in macrophages was evaluated. High PD-L2 expression in macrophages was associated with longer progression-free survival (PFS) and cancer-specific survival (CSS) and observed more often in females, non-heavy smokers, and patients with epidermal growth factor receptor (EGFR) mutations and those at a lower disease stage. Significant correlations were found more frequently in patients with EGFR mutations. Cell culture studies revealed that cancer cell-derived soluble factors induced PD-L2 overexpression in macrophages, suggesting the involvement of the JAK-STAT signaling pathway. The present findings suggest that PD-L2 expression in macrophages predicts PFS and CSS in lung adenocarcinoma without immunotherapy. [ABSTRACT FROM AUTHOR]

The pivotal role of the tumor microenvironment (TME) in the initiation and advancement of hepatocellular carcinoma (HCC) is widely acknowledged, as it fosters the proliferation and metastasis of HCC cells. Within the intricate TME of HCC, tumor-associated macrophages (TAMs) represent a significant constituent of non-malignant cells. TAMs engage in direct communication with cancer cells in HCC, while also exerting influence on other immune cells to adopt a tumor-supportive phenotype that facilitates tumor progression. Among the multifaceted mechanisms at play, the metabolic reprogramming of both tumor cells and macrophages leads to phenotypic alterations and functional modifications in macrophages. This comprehensive review elucidates the intricate interplay between cellular metabolism and macrophage phenotype/polarization, while also providing an overview of the associated signaling molecules and potential therapeutic strategies for HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Macrophages that infiltrate the cancer microenvironment are referred to as tumor-associated macrophages (TAMs). Phosphoprotein 1 (SPP1), also known as osteopontin, is a multifunctional secreted phosphorylated glycoprotein. In this review, we summarize the significance of TAMs in lung cancers and discuss the importance of SPP1 as a new marker for the protumor subpopulation of TAMs in lung adenocarcinoma. (1) The presence of TAMs is reportedly a poor prognostic factor in lung cancer. (2) We recently revealed that SPP1 expression on TAMs is correlated with poor prognosis and chemoresistance in lung adenocarcinoma. (3) SPP1 is a potentially useful marker for detecting monocyte-derived TAMs. Macrophages are a representative cell type in the tumor microenvironment. Macrophages that infiltrate the cancer microenvironment are referred to as tumor-associated macrophages (TAMs). TAMs exhibit protumor functions related to invasion, metastasis, and immunosuppression, and an increased density of TAMs is associated with a poor clinical course in many cancers. Phosphoprotein 1 (SPP1), also known as osteopontin, is a multifunctional secreted phosphorylated glycoprotein. Although SPP1 is produced in a variety of organs, at the cellular level, it is expressed on only a few cell types, such as osteoblasts, fibroblasts, macrophages, dendritic cells, lymphoid cells, and mononuclear cells. SPP1 is also expressed by cancer cells, and previous studies have demonstrated correlations between levels of circulating SPP1 and/or increased SPP1 expression on tumor cells and poor prognosis in many types of cancer. We recently revealed that SPP1 expression on TAMs is correlated with poor prognosis and chemoresistance in lung adenocarcinoma. In this review, we summarize the significance of TAMs in lung cancers and discuss the importance of SPP1 as a new marker for the protumor subpopulation of monocyte-derived TAMs in lung adenocarcinoma. Several studies have shown that the SPP1/CD44 axis contribute to cancer chemoresistance in solid cancers, so the SPP1/CD44 axis may represent one of the most critical mechanisms for cell-to-cell communication between cancer cells and TAMs. [ABSTRACT FROM AUTHOR]

Simple Summary: Resistance to chemotherapy is an important problem to be solved in breast cancer research. Tumor-associated macrophages (TAMs) contribute to breast cancer progression, including chemoresistance, and it is important to clarify the altered functions of macrophages following chemotherapy to improve prognosis of breast cancer patients. Here, we conducted in vitro experiments and immunohistochemistry in 116 breast carcinoma tissues to determine whether the secretion of heat shock protein (HSP) 70 from breast cancer cells following chemotherapy affects macrophage function. It was revealed that extracellular HSP70 levels increased following chemotherapy and enhanced the pro-tumorigenic effects of TAMs either directly or indirectly by regulating the expression of transforming growth factor (TGF)-β in breast cancer cells. Immunohistochemistry demonstrated that HSP70 functions as a poor prognostic factor in conjunction with macrophage infiltration. Targeting HSP70 may therefore be useful in regulating the tumor microenvironment in breast cancer tissues and improving the prognosis of breast cancer patients following chemotherapy. Tumor-associated macrophages (TAMs) contribute to tumor progression and chemoresistance; it is therefore important to clarify the altered functions of macrophages following chemotherapy. While extracellular heat shock protein (HSP) 70 is associated with therapeutic resistance, the effects of HSP70 on TAMs remain largely unknown. Here, we conducted in vitro experiments and immunohistochemistry in 116 breast carcinoma specimens to determine whether the secretion of HSP70 from breast cancer cells following chemotherapy affects macrophage function. It was revealed that the interaction of epirubicin (EPI)-exposed breast cancer cells with macrophages enhanced tumor progression, and EPI promoted the secretion of extracellular HSP70 from breast cancer cells. The expression of pro-tumorigenic macrophage marker CD163 was decreased in macrophages treated with a conditioned medium (CM) from HSP70-silenced breast cancer cells. Breast cancer cells treated with CM from HSP70-silenced breast cancer cells showed decreased expression of transforming growth factor (TGF)-β, and the pro-tumorigenic effects of macrophages were impaired when TGF-β signaling was inhibited. Immunohistochemistry demonstrated that HSP70 served as a poor prognostic factor in conjunction with macrophage infiltration. It was therefore concluded that extracellular HSP70 levels increased following chemotherapy and enhanced the pro-tumorigenic effects of TAMs, either directly or indirectly, by regulating TGF-β expression in breast cancer cells. [ABSTRACT FROM AUTHOR]

Kallikrein-related peptidase (KLK)6 is associated with inflammatory diseases and neoplastic progression. KLK6 is aberrantly expressed in several solid tumors and regulates cancer development, metastatic progression, and drug resistance. However, the function of KLK6 in the tumor microenvironment remains unclear. This study aimed to determine the role of KLK6 in the tumor microenvironment. Here, we uncovered the mechanism underlying KLK6-mediated cross-talk between cancer cells and macrophages. Compared with wild-type mice, KLK6−/− mice showed less tumor growth and metastasis in the B16F10 melanoma and Lewis lung carcinoma (LLC) xenograft model. Mechanistically, KLK6 promoted the secretion of tumor necrosis factor-alpha (TNF-α) from macrophages via the activation of protease-activated receptor-1 (PAR1) in an autocrine manner. TNF-α secreted from macrophages induced the release of the C-X-C motif chemokine ligand 1 (CXCL1) from melanoma and lung carcinoma cells in a paracrine manner. The introduction of recombinant KLK6 protein in KLK6−/− mice rescued the production of TNF-α and CXCL1, tumor growth, and metastasis. Inhibition of PAR1 activity suppressed these malignant phenotypes rescued by rKLK6 in vitro and in vivo. Our findings suggest that KLK6 functions as an important molecular link between macrophages and cancer cells during malignant progression, thereby providing opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

The role of the immune system in tumor progression has been the subject of research for more than 100 years since Paul Ehrlich hypothesized that the presence of the immune system limits the occurrence of cancer. One of the mechanisms hindering the initiation and progression of the tumor is the cytotoxic activity of macrophages; however, in some cases, it is not sufficient to control tumorigenesis. This may be due to both the development of resistance of tumor cells to the antitumor activity of macrophages and the development of a tolerant phenotype of macrophages that do not have sufficient antitumor activity. In this work, the lung cancer cells resistant to the cytotoxic action of macrophages were obtained and characterized for the first time, and the genes associated with the observed changes were identified. Understanding the mechanisms of resistance of tumor cells to the cytotoxic activity of macrophages and the peculiarities of its manifestation in a tumor environment is critically important for improving the effectiveness of the existing methods of cancer treatment and developing novel methods for tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Tumour heterogeneity refers to the complexity of cell subpopulations coexisting within the tumour microenvironment (TME), such as proliferating tumour cells, tumour stromal cells and infiltrating immune cells. The bidirectional interactions between cancer and the surrounding microenvironment mark the tumour survival and promotion functions, which allow the cancer cells to become invasive and initiate the metastatic cascade. Importantly, these interactions have been closely associated with metabolic reprogramming, which can modulate the differentiation and functions of immune cells and thus initiate the antitumour response. The purpose of this report is to review the CD36 receptor, a prominent cell receptor in metabolic activity specifically in fatty acid (FA) uptake, for the metabolic symbiosis of cancer–macrophage. In this review, we provide an update on metabolic communication between tumour cells and macrophages, as well as how the immunometabolism indirectly orchestrates the tumour metastasis. [ABSTRACT FROM AUTHOR]

Background: A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10) plays a role in extracellular matrix and correlates with Weill–Marchesani syndrome. However, its role in gastric cancer remains unknown. Thus, we started this research to unveil the role of ADAMTS10 in gastric cancer (GC). Methods: The expression of ADAMTS10 in GC was analyzed by immunohistochemical staining and quantitative RT-PCR (qRT-PCR). The effects of ADAMTS10 inhibiting GC cell progression were conducted by functional experiments in vitro and in vivo. Flow cytometry was used to discover changing of cell cycle, apoptosis and ROS by ADAMTS10 in GC cell. Western blot was applied to identify targets of ADAMTS10. Western blot, qRT-PCR and flow cytometry were applied to discover the effect of ADAMT10 on THP1. Results: ADAMTS10 expression was downregulated in GC tissue and patients with low ADAMTS10 levels had poorer overall survival. ADAMTS10 overexpression altered cell cycle, promoted apoptosis, and inhibited proliferation, migration, and invasion in vitro and in vivo. ADAMTS10 regulated TXNIP and ROS through the JAK/STAT/c-MYC pathway. Decreasing TXNIP and ROS reversed the inhibitory effect of ADAMTS10 on cell migration and invasion in vitro. ADAMTS10 secreted by GC cells was absorbed by THP1 and regulated TXNIP and ROS in THP1. ADAMTS10 secreted by GC cells inhibited macrophage M2 polarization. Conclusions: These results suggest that ADAMTS10 targets TXNIP and ROS via the JAK/STAT/c-MYC pathway and that may play important roles in GC progression and macrophage polarization which indicates that ADAMTS10 can be a potential survival marker for gastric cancer. [ABSTRACT FROM AUTHOR]

Recent molecular profiling revealed that cancer-associated fibroblasts (CAFs) are essential for matrix remodeling and tumor progression. Our study aimed to investigate the role of flavin-containing monooxygenase 2 (FMO2) in epithelial ovarian cancer (EOC) as a novel CAF-derived prognostic biomarker. Primary fibroblasts were isolated from EOC samples. Microdissection and single-cell RNA sequencing (scRNA-seq) datasets (including TCGA, GSE9891, GSE63885, GSE118828 and GSE178913) were retrieved to determine the expression profiles. Gene set enrichment analysis (GSEA) was used to explore the correlation between FMO2 and stromal activation as well as immune infiltration. The predictive value of FMO2 and combined macrophage infiltration level was verified in an independent EOC cohort (n = 113). We demonstrated that FMO2 was upregulated in tumor stroma and correlated with fibroblast activation. Besides, FMO2 had the predictive power for worse clinical outcome of EOC patients. In the mesenchymal subtype of EOC, the FMO2-defined signature revealed that FMO2 contributed to infiltration of tumor-infiltrating lymphocytes. Moreover, we confirmed the positive correlation between FMO2 and CD163+ cell infiltration level in EOC tissues, and showed that combination of FMO2 expression with CD163+ cell infiltration level in the tumor stroma could predict poor overall survival (HR = 3.63, 95% CI = 1.93–6.84, p = 0.0008). Additionally, FMO2 also predicted the prognosis of patients with ovarian cancer based on the expression of immune checkpoints (such as PD-L1 and PD1). Our results address the tumor-supporting role of FMO2 in EOC and its association with immune components, and it might be a prospective target for stroma-oriented therapies against EOC. • FMO2 contributed to the infiltration of macrophage. • Combination of FMO2 expression with CD163+ cell infiltration in stroma could predict poor overall survival. • FMO2 predicted the prognosis of patients with ovarian cancer based on the expression of immune checkpoints. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review, we discuss the current understanding of pro- and anticancer immune responses in the tumor immune microenvironment of pancreatic ductal adenocarcinoma. We describe the duality and complexity of immune cell functions in the tumor microenvironment and also illustrate therapeutic approaches that modulate the antitumor immune response. Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic tumor and is associated with poor prognosis and treatment response. The tumor microenvironment (TME) is recognized as an important factor in metastatic progression across cancers. Despite extensive study of the TME in PDAC, the cellular and molecular signaling networks remain poorly understood, largely due to the tremendous heterogeneity across tumors. While earlier work characterized PDAC as an immunologically privileged tumor poorly recognized by the immune system, recent studies revealed the important and nuanced roles of immune cells in the pathogenesis of PDAC. Distinct lymphoid, myeloid, and stromal cell types in the TME exert opposing influences on PDAC tumor trajectory, suggesting a more complex organization than the classical "hot" versus "cold" tumor distinction. We review the pro- and antitumor immune processes found in PDAC and briefly discuss their leverage for the development of novel therapeutic approaches in the field. [ABSTRACT FROM AUTHOR]

Macrophage-based nanomedicine represents an emerging powerful strategy for cancer therapy. Unfortunately, some obstacles and challenges limit the translational applications of macrophage-mediated nanodrug delivery system. For instance, tracking and effective cell delivery for targeted tumor sites remain to be overcome, and controlling the states of macrophages is still rather difficult due to their plastic nature in response to external stimuli. To address these critical issues, here, we reported a novel type of silver nanoclusters (AgNCs) with excellent fluorescent intensity, especially long-lasting cell labeling stability after endocytosis by macrophages, indicating promising applications in tracking macrophage-based nanomedicine delivery. Our mechanistic investigations uncovered that these merits originate from the escape of AgNCs from lysosomal degradation within macrophages. In addition, the AgNCs would prime the M1-like polarization of macrophages (at least in part) through the toll-like receptor 4 signaling pathway. The engineered macrophages laden with AgNCs could be employed for lung metastasis breast cancer treatment, showing the effective targeting propensity to metastatic tumors, remarkable regulation of tumor immune microenvironment and inhibition of tumor growth. Collectively, AgNC-trained macrophages appear to be a promising strategy for tumor immune-microenvironment regulation, which might be generalized to a wider spectrum of cancer therapeutics. [Display omitted] [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor-associated macrophages and monocyte myeloid-derived immunosuppressive cells are associated with bad prognosis in malignant pleural mesothelioma (MPM). This study shows that peripheral blood monocytes can, nevertheless, be cytotoxic for MPM tumor cells. This cytotoxic activity that involves direct cell-to-cell contact can be improved with a lysine deacetylase inhibitor (VPA), opening new prospects for further improvement of still unsatisfactory MPM therapies. The composition of the tumor microenvironment (TME) mediates the outcome of chemo- and immunotherapies in malignant pleural mesothelioma (MPM). Tumor-associated macrophages (TAMs) and monocyte myeloid-derived immunosuppressive cells (M-MDSCs) constitute a major fraction of the TME. As central cells of the innate immune system, monocytes exert well-characterized functions of phagocytosis, cytokine production, and antibody-dependent cell-mediated cytotoxicity (ADCC). The objective of this study was to evaluate the ability of monocytes to exert a direct cytotoxicity by cell-to-cell contact with MPM cells. The experimental model is based on cocultures between human blood-derived monocytes sorted by negative selection and mesothelioma cell lines. Data show (i) that blood-derived human monocytes induce tumor cell death by direct cell-to-cell contact, (ii) that VPA is a pharmacological enhancer of this cytotoxic activity, (iii) that VPA increases monocyte migration and their aggregation with MPM cells, and (iv) that the molecular mechanisms behind VPA modulation of monocytes involve a downregulation of the membrane receptors associated with the M2 phenotype, i.e., CD163, CD206, and CD209. These conclusions, thus, broaden our understanding about the molecular mechanisms involved in immunosurveillance of the tumor microenvironment and open new prospects for further improvement of still unsatisfactory MPM therapies [ABSTRACT FROM AUTHOR]

Simple Summary: The tumor microenvironment determines the prognosis and outcome for cancer patients. Herein, tumor-associated macrophages are not only highly abundant, but also play a crucial role in shaping a tumor-supporting microenvironment. Both their recruitment to the tumor as well as their functional polarization toward a pro-tumorigenic phenotype are mediated by tumor-derived factors including microRNAs. However, the impact of most microRNAs on the tumor cell-macrophage crosstalk remains to be elucidated. Thus, we reached out to investigate the role of hsa-miR-200c-3p (miR-200c) in tumor cell–macrophage interactions, as it was shown to be differentially expressed during cancer progression and metastasis. miR-200c was highly expressed in MCF7 breast tumor cells compared to macrophages. Furthermore, we identified a CD36-dependent uptake of miR-200c, derived from apoptotic tumor cells, into macrophages. In macrophages, elevated miR-200c levels reduced the expression of numerous migration-associated mRNAs, consequently reducing the capacity of macrophages to infiltrate into tumor spheroids. Finally, a distinct signature of miR-200c-repressed, predicted targets was identified, which strongly correlated with tumor infiltration. Targeting the miR-200c transfer from dying tumor cells to macrophages might therefore provide the opportunity to specifically modulate tumor-associated macrophage recruitment. Macrophages constitute a major part of the tumor-infiltrating immune cells. Within the tumor microenvironment, they acquire an alternatively activated, tumor-supporting phenotype. Factors released by tumor cells are crucial for the recruitment of tumor-associated macrophages. In the present project, we aimed to understand the role of hsa-miR-200c-3p (miR-200c) in the interplay between tumor cells and macrophages. To this end, we employed a coculture system of MCF7 breast tumor cells and primary human macrophages and observed the transfer of miR-200c from apoptotic tumor cells to macrophages, which required intact CD36 receptor in macrophages. We further comprehensively determined miR-200c targets in macrophages by mRNA-sequencing and identified numerous migration-associated mRNAs to be downregulated by miR-200c. Consequently, miR-200c attenuated macrophage infiltration into 3-dimensional tumor spheroids. miR-200c-mediated reduction in infiltration further correlated with a miR-200c migration signature comprised of the four miR-200c-repressed, predicted targets PPM1F, RAB11FIB2, RDX, and MSN. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the interactions between osteosarcoma (OS) and M1 macrophages infiltrated into the tumor microenvironment and to explore the underlying mechanisms whereby M1 macrophages influence the growth of OS, so that novel treatments of OS can be developed. A transwell co-culture system, an indirect conditioned medium culture system and two orthotopic bearing OS models were established to assess for the interplay between M1 macrophages and OS. We found that the co-culture of M1 macrophages with OS cells significantly inhibited the growth of the tumor cells by inducing apoptosis. Furthermore, HSPA1L secreted by M1 macrophages exerted this anti-tumor effect through the IRAK1 and IRAK4 pathways. LGALS3BP secreted by OS cells bound to the ligand LGALS3 on M1 macrophages and thereby induced the secretion of Hspa11 via Akt phosphorylation. In vivo experiments demonstrated that the culture supernatant of OS-stimulated M1 macrophages significantly inhibited the growth of OS, whereas silencing Lgals3bp promoted the progression of OS. In conclusion, OS modifies the phenotype of tumor-associated macrophages (TAMs) and thereby influences the apoptosis of OS cells through soluble factors. The modulation of TAMs may be a promising and effective therapeutic approach in OS. [ABSTRACT FROM AUTHOR]

Invasion and metastasis of breast cancer cells is an important cause of death in breast cancer patients. In the tumor microenvironment, M2 polarization of macrophages can promote the invasion and metastasis of tumor cells. OVOL2 is an evolutionarily conserved transcription regulator, but its effect in macrophages has not been described previously. The aim of this study was to investigate the effects of OVOL2 on macrophage polarity and the role of these effects in the tumor metastasis. We found that overexpression of OVOL2 in macrophages significantly inhibited M2 polarization and thus inhibits breast cancer metastasis. We propose a novel mechanism in which OVOL2 inhibits M2 polarization of macrophages and thus reduces their ability to induce invasion and metastasis of breast cancer. By shedding new light on the regulation of metastasis in cancers, our study provides a new strategy for the targeted therapy of cancer. [ABSTRACT FROM AUTHOR]

Leucine-rich repeat kinase2 (LRRK2) influences the host immune responses and correlates with the pathogenesis of inflammation, cancer as well as Parkinson' Disease. Herein, we explored the oncogenic role of LRRK2 at pan-cancer level and validated the analysis by single cell RNA-sequencing and in-vitro experiments. As a result, LRRK2 significantly correlated with the survival events. Specifically, LRRK2 increased the risk of Low-Grade Glioma whereas improved the survival probability of patients with Skin Cutaneous Melanoma. Gene set enrichment analysis demonstrated the involvement of LRRK2 in the host immune responses. Within the tumor microenvironment, LRRK2 was positively associated with the recruitment of macrophages. Furthermore, scRNA-seq and co-culture experiments demonstrated that LRRK2 deficiency impaired macrophage functions, and influenced the neoplastic progression in a cancer type-specific manner. Therefore, the present study provided a therapeutic strategy for LGG based on the interference with LRRK2 expression and activity to prevent macrophage recruitment and promote tumor eradication. • LRRK2 correlated with the recruitment of tumor-associated macrophages. • LRRK2 influenced the cross-talking within the tumor microenvironment in a cancer type-dependent manner. • LRRK2 deficiency facilitated M2 transition of macrophages and promoted the neoplastic virtues of cancer cells at the early stage of tumor progression. [ABSTRACT FROM AUTHOR]

Macrophages of the M2 phenotype in malignant tumors significantly aid tumor progression and metastasis, as opposed to the M1 phenotype that exhibits anti-cancer characteristics. Raising the ratio of M1/M2 is thus a promising strategy to ameliorate the tumor immunomicroenvironment toward cancer inhibition. We report here that tumor necrosis factor superfamily-15 (TNFSF15), a cytokine with anti-angiogenic activities, is able to facilitate the differentiation and polarization of macrophages toward M1 phenotype. We found that tumors formed in mice by Lewis lung carcinoma (LLC) cells artificially overexpressing TNFSF15 exhibited retarded growth. The tumors displayed a greater percentage of M1 macrophages than those formed by mock-transfected LLC cells. Treatment of mouse macrophage RAW264.7 cells with recombinant TNFSF15 led to augmentation of the phagocytic and pro-apoptotic capacity of the macrophages against cancer cells. Mechanistically, TNFSF15 activated STAT1/3 in bone marrow cells and MAPK, Akt and STAT1/3 in naive macrophages. Additionally, TNFSF15 activated STAT1/3 but inactivated STAT6 in M2 macrophages. Modulations of these signals gave rise to a reposition of macrophage phenotypes toward M1. The ability of TNFSF15 to promote macrophage differentiation and polarization toward M1 suggests that this unique cytokine may have a utility in the reconstruction of the immunomicroenvironment in favor of tumor suppression. [ABSTRACT FROM AUTHOR]

The glioma microenvironment is heavily infiltrated by non-neoplastic myeloid cells, including bone marrow–derived macrophages and central nervous system-resident microglia. As opposed to executing the antitumor functions of immune surveillance, antigen presentation, and phagocytosis, these tumor-associated myeloid cells are co-opted to promote an immunosuppressive milieu and support tumor invasion and angiogenesis. This review explores evolving evidence and the research paradigms used to determine the interplay of tumor genetics, immune cell composition, and immune function in gliomas. Understanding these cells and how they are reprogrammed will be instrumental in finding new and effective treatments for these lethal tumors. [ABSTRACT FROM AUTHOR]

We investigated the fundamental function of the lung cancer tumour microenvironment. Proteasome inhibition has emerged as a clinically successful anti-cancer therapeutic strategy, with the antineoplastic medication bortezomib showing high efficacy against multiple cancers. Tumour-associated macrophages (TAMs), which migrate to tumour stroma, are known to promote cell proliferation, apoptosis, and metastasis within the lung cancer microenvironment. However, the specific interaction of macrophages, lung cancer cells, and bortezomib are still unclear. Most in vitro cell cultures are traditionally grown in a two-dimensional (2D) culture system, although 3D cultures have demonstrated greater success in terms of drug response, gene expression and viability. Therefore, to elucidate the role of macrophages, we aimed to establish a co-culture model in both 2D and 3D cultures using A549 human lung cancer cells and THP-1 derived macrophages. Apoptotic effects were analysed using the Annexin V-PI method. Since NF-kB and TNF-a play important roles in the anti-proliferation and apoptosis pathways, the levels of NF-kB and TNF-a mRNA expression were measured. As a result, bortezomib significantly increased cell apoptosis in cells co-cultured with M0 macrophages. IL-1ß cytokine levels also increased, and NF-kB mRNA expression levels decreased. Understanding the mechanisms that modulate the tumour microenvironment may facilitate the development of novel anticancer therapies. The utilisation of TAMs may improve the successful treatment of lung cancer and warrants further study. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is a common type of the Non-Hodgkin lymphomas (NHLs) formed by the neoplastic transformation of mature B cells. As the first-line therapeutics, CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy and R-CHOP (Rituximab + CHOP), either using alone or in combination with GM-CSF, have achieved great efficacy in DLBCL patients. However, the underlying mechanisms are still largely unknown. Methods: In the present study, the combination use of CHOP and R-CHOP with GM-CSF was used to evaluate their effects on the tumor immune microenvironment of DLBCL. CHOP and R-CHOP administration was found to inhibit the growth and metastasis of DLBCL, with a higher efficacy in R-CHOP-challenged DLBCL mice. The anti-tumor effect of CHOP and R-CHOP was further amplified by GM-CSF. Results: CHOP and R-CHOP therapeutics potentiated the anti-tumor properties of macrophages, as evidenced by the increased M1 macrophage and the decreased M2 macrophage accumulation in DLBCL-bearing mice. In a co-culture system, macrophages primed with CHOP and R-CHOP therapeutics inhibited multiple malignant behaviors of DLCBL cells. Mechanistically, CHOP/R-CHOP suppressed the activation of AKT signaling. These anti-tumor effects of CHOP/R-CHOP were all augmented by GM-CSF. Conclusions: Our work provided new insights into the immune-regulatory roles of CHOP and R-CHOP in the treatment of DLBCL, as well as the synergistic effects of GM-CSF in CHOP and R-CHOP therapeutics. Although our results suggest the synergistic effect of GM-CSF on DLBCL already sensitive to CHOP and R-CHOP, however, future studies are warranted to explore the role of GM-CSF on R-CHOP-resistant DLBCL. Trial registration Not applicable. [ABSTRACT FROM AUTHOR]

As one of the most fatal gastrointestinal cancers, pancreatic cancer (PC) has a long-term survival rate that has shown limited improvement during recent decades and remains dismal. The poor prognosis is attributed to challenges in early detection, low opportunity for radical resection and resistance to chemotherapy and radiation. Macrophages are one of the most abundant infiltrating immune cells in PC stroma, and they can crosstalk with cancer cells, adipocytes and other stromal cells to modulate metabolism, inflammation and immune status, create an immunosuppressive tumor microenvironment (TME), and ultimately facilitate tumor initiation and progression. In this review, we summarize recent advances in our understanding of macrophage origin, distribution and polarization, as well as provide a thorough review of the role macrophages in PC carcinogenesis and development, as well as the underlying molecular mechanism. Additionally, we investigated macrophage targets in preclinical and clinical trials to evaluate their potential therapeutic value in PC. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment that can be polarized into different phenotypes, including tumor-inhibiting M1 macrophages and tumor-promoting M2 macrophages. To elucidate the biological and clinical significance of M2 TAMs in non-small-cell lung cancer (NSCLC), a comprehensive clinical assessment of the tissue distribution of M2 TAMs was performed. The tissue distribution of M2 TAMs was retrospectively analyzed using CD163 immunohistochemistry in 160 consecutive patients who underwent NSCLC resection. Tumor proliferation was evaluated via the Ki-67 proliferation index. The results revealed that the stromal density of M2 TAMs was significantly associated with the C-reactive protein (CRP) level (P=0.0250), the Ki-67 proliferation index (P=0.0090) and invasive size (P=0.0285). Furthermore, the stromal M2 TAM density was significantly associated with tumor differentiation (P=0.0018), lymph node metastasis (P=0.0347) and pathological stage (P=0.0412). The alveolar M2 TAM density was also significantly associated with the CRP level (P=0.0309), invasive size (P<0.0001), tumor differentiation (P=0.0192), tumor status (P=0.0108) and pathological stage (P=0.0110). By contrast, no association was observed between islet M2 TAM density and the aforementioned biological and clinical factors. In regards to prognosis, disease-free survival rate was significantly lower in patients with stromal M2 TAM-high tumors (P=0.0270) and in those with alveolar M2 TAM-high tumors (P=0.0283). Furthermore, the overall survival rate was also significantly lower in patients with stromal M2 TAM-high tumors (P=0.0162) and in those with alveolar M2 TAM-high tumors (P=0.0225). Therefore, during NSCLC progression, M2 TAMs may induce tumor cell aggressiveness and proliferation and increase metastatic potential, resulting in a poor prognosis in patients with NSCLC. [ABSTRACT FROM AUTHOR]

• Chemokines are critical modulators in the tumor milieu. • Cancer cells release chemokines that can promote tumor progression and metastasis. • Chemokines derived from cancer cells are potential targets for cancer immunotherapy. Beyond their essential role in leukocyte homing in the context of inflammation, chemokines orchestrate the host response to cancer progression. Chemokines are key accelerators in the amplification of inflammatory signals and metastasis in the distal zone of tumors, indicating possible immune editing of tumor cells in the microenvironment. This review summarizes the main macrophage-attracting chemokines secreted from cancer cells and how these mediators can be targeted to improve cancer immunotherapy in multiple cancer types. [ABSTRACT FROM AUTHOR]

Background: Tumor-associated macrophages (TAMs) are known to play important roles in the initiation and progression of human cancers, as well as in angiogenesis. TAMs are considered as main components of the tumor microenvironment. Targeting TAMs may serve as a therapeutic strategy for the treatment of cancer. In this review, the signaling pathways, origin, function, polarization and clinical application of TAMs are discussed. The role of TAMs in tumor initiation, progression, angiogenesis, invasion and metastasis are also emphasized. In addition, a variety of clinical and pre-clinical approaches to target TAMs are discussed. Conclusions: Clinical therapeutic approaches that show most promise include blocking the extravasation of TAMs along with using TAMs as diagnostic biomarkers for cancer progression. The targeting of TAMs in a variety of clinical settings appears to be a promising strategy for decreasing metastasis formation and for improving patient outcome. [ABSTRACT FROM AUTHOR]

Background: β2-adrenoceptors (β2-ARs) are expressed on the surface of immune cells, including tumor-associated macrophages (TAMs). Previous studies have demonstrated that the expression of β2-ARs in hepatocellular carcinoma (HCC) is significantly increased in vitro. However, the role of β2-AR in M2-polarized macrophages remains unclear. G protein-coupled receptor kinase 2 (GRK2) can regulate G protein-coupled receptor (GPCR). Previous studies showed that down-regulation of GRK2 in HCC contributes the HCC progression, but it still remains unclear whether the regulation of β2-AR in M2-polarized macrophages by GRK2 can promote HCC. Purpose: The present study was designed to investigate the role of activated β2-AR in M2-polarized macrophages in the HCC progression and GRK2 regulatory effect, as well as the underlying mechanisms involved. Results: The results demonstrated that the M2-polarized macrophages were increased with HCC progression. In vitro, the activation of β2-AR by terbutaline in M2-polarized macrophages elevated the proliferative, migratory and invasive attributes of HCC cells. Furthermore, GRK2 down-regulation in β2-AR activated M2-polarized macrophages activated the downstream cyclic adenosine monophosphate (cAMP)/protein kinase A/cAMP-response element binding protein and cAMP/interleukin-6/signal transducer and the activator of transcription 3 signaling pathways, contributing to the secretion of tumor-associated cytokines, and thus resulting in the promotion of malignant biological behavior in HCC cells. Conclusion: These findings suggest that the regulation of β2-AR occurs through the silencing of GRK2 in M2-polarized macrophages, which is conducive to HCC development, through its engagement in the activation of downstream signaling. [ABSTRACT FROM AUTHOR]

Immune dysfunction often occurs in malignant pleural effusion (MPE). In our previous study, TGF-β derived predominantly from macrophages plays an important role in impairing T cell cytotoxicity in MPE. Therefore, we aimed to investigate whether other immunoregulatory cells and factors mediated TGF-β secretion from macrophages, involved in the immunosuppressive microenvironment of MPE, and to provide clues for potential immune therapy for MPE as well. We found that CCL22 level in MPE was significantly higher than that in non-malignant pleural effusion. The high level of CCL22 was closely associated with poor survival in MPE patients with lung cancer. CCL22 was dominantly produced by tumor-associated macrophages (TAMs) in MPE. Meanwhile, TAM-derived TGF-β mediated CCL22 expression in TAMs via c-Fos. CCL22 promoted the recruitment of regulatory T cells (Tregs) in MPE. Lastly, Treg-secreted high level of IL-8 further induced TGF-β production from TAMs, and promoted the immunosuppressive tumor microenvironment in MPE. Our results indicate that macrophage-derived CCL22 plays an important role in the immunosuppressive tumor microenvironment via IL-8 in MPE. [ABSTRACT FROM AUTHOR]

Macrophages play an important role in tissue development and homeostasis. They serve as a nexus between adaptive and innate immunity, and employ considerable plasticity. In cancer, they play a pivotal role in chronic inflammation and tumor growth either by directly stimulating the proliferation of cancer cells or by producing angiogenic and lymphangiogenic factors. Although numerous immune cells play an important role in the tumor microenvironment, tumor-associated macrophages (TAMs) are by far the most extensively studied. A better understanding of the role of TAMs in mediating chemo- and radiotherapy resistance and suppressing immunosurveillance has led to numerous strategies targeting TAMs as an anticancer therapy either by targeting them directly or by polarizing TAMs toward a tumoricidal phenotype. [ABSTRACT FROM AUTHOR]

Abstract Tumors may include a high proportion of immune modulatory cells and molecules that restrain the anti-cancer response. Activation of T cells to eliminate cancer cells within the immune-suppressive tumor microenvironment remains a challenge. We have shown that C57BL/6 J peritoneal cell culture models features of macrophage-dense tumors as TCR ligation fails to activate T cells unless IFNγ is neutralized or iNOS is inhibited. We tested other forms of T cell activation and found phytohemagglutinin (PHA) distinctive in the ability to markedly expand CD8 T cells in this model. IFNγ or iNOS inhibition was not necessary for this response. PHA triggered less IFNγ production and inhibitory PD-L1 expression than TCR ligation. Macrophages and CD44hi T cells bound PHA. Spleen T cell responses to PHA were markedly enhanced by the addition of peritoneal cells revealing that macrophages enhance T cell expansion. That PHA increases CD8 T cell responses within macrophage-dense culture suggests this mitogen might enhance anti-tumor immunity. [ABSTRACT FROM AUTHOR]

Cancer stem cells are a small population of cells with the potential for self-renewal and multi-directional differentiation and are an important source of cancer initiation, treatment resistance, and recurrence. Epithelial–mesenchymal transition (EMT) is a process in which epithelial cells lose their epithelial phenotype and convert to mesenchymal cells. Recent studies have shown that cancer cells undergoing EMT can become stem-like cells. Many kinds of tumors are associated with chronic inflammation, which plays a role in tumor progression. Among the various immune cells mediating chronic inflammation, macrophages account for ~30%–50% of the tumor mass. Macrophages are highly infiltrative in the tumor microenvironment and secrete a series of inflammatory factors and cytokines, such as transforming growth factor (TGF)-β, IL-6, IL-10, and tumor necrosis factor (TNF)-α, which promote EMT and enhance the stemness of cancer cells. This review summarizes and discusses recent research findings on some specific mechanisms of tumor-associated macrophage-derived cytokines in EMT and cancer stemness transition, which are emerging targets of cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Recent progress in molecular analysis has advanced the understanding of medulloblastoma (MB) and is anticipated to facilitate management of the disease. MB is composed of 4 molecular subgroups: WNT, SHH, Group 3, and Group 4. Macrophages play a crucial role in the tumor microenvironment; however, the functional role of their activated phenotype (M1/M2) remains controversial. Herein, we investigate the correlation between tumor-associated macrophage (TAM) recruitment within the MB subgroups and prognosis.Methods: Molecular subgrouping was performed by a nanoString-based RNA assay on retrieved snap-frozen tissue samples. Immunohistochemistry (IHC) and immunofluorescence (IF) assays were performed on subgroup identified samples, and the number of polarized macrophages was quantified from IHC. Survival analyses were conducted on collected clinical data and quantified macrophage data.Results: TAM (M1/M2) recruitment in SHH MB was significantly higher compared to that in other subgroups. A Kaplan-Meier survival curve and multivariate Cox regression demonstrated that high M1 expressers showed worse overall survival (OS) and progression-free survival (PFS) than low M1 expressers in SHH MB, with relative risk (RR) values of 11.918 and 6.022, respectively.Conclusion: M1 rather than M2 correlates more strongly with worse outcome in SHH medulloblastoma. [ABSTRACT FROM AUTHOR]

Cutaneous melanoma is an aggressive cancer and its onset and growth are associated, through direct and indirect interactions, with the cancer microenvironment. The microenvironment comprises a dynamic complex of numerous types of cells (due to histogenesis) that constantly interact with each other through multiple cytokines and signaling proteins. Macrophages are one of the most thoroughly studied pleiotropic cells of the immune system. One of their major cytophysiological functions is their involvement in phagocytosis. Previous studies examining the microenvironment of melanomas and tumor-associated macrophages have revealed that they are involved in all stages of melanomagenesis. In the case of cancer initiation, they form an inflammatory microenvironment and then suppress the anticancer activity of the immune system, stimulate angiogenesis, enhance migration and invasion of the cancer cells, and ultimately contribute to the metastatic process. The present review provides a detailed overview on the function of macrophages in the melanoma microenvironment. [ABSTRACT FROM AUTHOR]

Tumors are often comprised of microenvironments (TMEs) with a high proportion of cells and molecules that regulate immunity. Peritoneal cavity (PerC) cell culture reproduces key features of TMEs as lymphocyte proliferation is suppressed by PerC macrophages (Mϕs). We monitored the expression of T cell stimulatory (Class II MHC, B7) and inhibitory (PD-L1) molecules by PerC APCs before and after culture and report here that IFNγ-driven PD-L1 expression increased markedly on PerC Mϕs after TCR ligation, even more so than seen with direct APC activation by LPS. Considering the high APC composition of and pronounced PD-L1 expression by PerC cells, it was surprising that blocking PD-1/PD-L1 interaction by mAb neutralization or genetic ablation did not relieve suppression. This result parallels TME challenges observed in the clinic and validates the need for further study of this culture model to inform strategies to promote anti-tumor immunity. [ABSTRACT FROM AUTHOR]

As a result of therapy-induced apoptosis, peripheral blood monocytes are recruited to tumors, where they become tumor-associated macrophages (TAMs). To date, few studies have investigated noninvasive molecular imaging for assessment of macrophage infiltration in response to therapy-induced apoptosis. Here, noninvasive assessment of changes in tumor accumulation of TAMs was proposed as a new way to measure early tumor response to anticancer therapy. Three different nanoparticles, QD710-Dendron quantum dots (QD710-D), Ferumoxytol, and PG-Gd-NIR813, were used for near-infrared fluorescence imaging, T2-weighted magnetic resonance imaging, and dual optical/T1-weighted MR imaging, respectively, in the MDA-MB-435 tumor model. Treatment with Abraxane induced tumor apoptosis and infiltrating macrophages. In spite of markedly different physicochemical properties among the nanoparticles, in vivo imaging revealed increased uptake of all three nanoparticles in Abraxane-treated tumors compared with untreated tumors. Moreover, imaging visualized increased uptake of QD710-D in MDA-MB-435 tumors but not in drug-resistant MDA-MB-435R tumors grown in the mice treated with Abraxane. Our results suggest that infiltration of macrophages due to chemotherapy-induced apoptosis was partially responsible for increased nanoparticle uptake in treated tumors. Noninvasive imaging techniques in conjunction with systemic administration of imageable nanoparticles that are taken up by macrophages are a potentially useful tool for assessing early treatment response. [ABSTRACT FROM AUTHOR]

The cell-death programme, apoptosis, iswell established as a tumour suppressor mechanism. Paradoxically, high levels of apoptosis in tumours are closely coupled with poor prognosis. Indeed, where it has been studied, cell loss is a striking feature of high-grade cancers, illustrating the importance of considering malignant disease as an imbalance between cell gain and cell loss that favours cell gain rather than as a unidirectional disorder of cell gain alone. In addition to orchestrating cell loss, apoptosis can signal regenerative responses-for example compensatory proliferation-in neighbouring cells. Accumulating evidence suggests that normal tissue repair and regenerative processes are hijacked in the malignant tissue microenvironment such that cancer may be likened to a 'wound that fails to stop repairing'. We have proposed that a critical requirement for the successful growth, progression and re-growth of malignant tumours is a complex milieu, conceptually termed the 'onco-regenerative niche', which is composed, in addition to transformed neoplastic cells, of a network of normal cells and factors activated as if in tissue repair and regeneration. Our work is based around the hypothesis that tumour cell apoptosis, macrophage activation and endothelial activation are key, interlinked elements of the onco-regenerative niche and that apoptotic tumour cell-derived extracellular vesicles provide critical intercellular communication vehicles of the niche. In aggressive B-cell lymphoma, tumour cell apoptosis promotes both angiogenesis and the accumulation of pro-tumour macrophages in the lymphoma microenvironment. Furthermore, apoptotic lymphoma-derived extracellular vesicles have potent pro-tumour potential. These findings have important implications for the roles of apoptosis in regulation of malignant diseases and for the efficacy of apoptosis-inducing anti-cancer therapies. This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. [ABSTRACT FROM AUTHOR]

Myeloid cells are increasingly being recognized as central players orchestrating or suppressing antitumor immune responses. With the advent of high-resolution analytical methods such as single-cell technologies, we now appreciate the heterogeneity and complexity of the myeloid compartment in the context of cancer. Because of their highly plastic nature, targeting myeloid cells has shown promising results either as a monotherapy or in combination with immunotherapy in preclinical models and cancer patients. However, the complexity of myeloid cell cellular crosstalk and molecular networks contributes to our poor understanding of the different myeloid cell subsets in tumorigenesis, which makes targeting myeloid cells challenging. Here, we summarize varied myeloid cell subsets and their contribution to tumor progression with a main focus on mononuclear phagocytes. The top three unanswered questions challenging the field of myeloid cells and cancer in the era of cancer immunotherapy are addressed. Through these questions, we discuss how myeloid cell origin and identity influence their function and disease outcomes. Different therapeutic strategies used to target myeloid cells in cancer are also addressed. Finally, the durability of myeloid cell targeting is interrogated by examining the complexity of resultant compensatory cellular and molecular mechanisms. [ABSTRACT FROM AUTHOR]

Impaired immune function has been implicated in the declining health and higher incidence of cancer in the elderly. However, age-related changes to immunity are not completely understood. Neutrophils and macrophages represent the first line of defence yet their ability to phagocytose pathogens decrease with aging. Cytotoxic T lymphocytes are critical in eliminating tumors, but T cell function is also compromised with aging. T cell responses can be regulated by macrophages and may depend on the functional phenotype macrophages adopt in response to microenvironmental signals. This can range from pro-inflammatory, anti-tumorigenic M1 to anti-inflammatory, pro-tumorigenic M2 macrophages. Macrophages in healthy elderly adipose and hepatic tissue exhibit a more pro-inflammatory M1 phenotype compared to young hosts whilst immunosuppressive M2 macrophages increase in elderly lymphoid tissues, lung and muscle. These M2-like macrophages demonstrate altered responses to stimuli. Recent studies suggest that neutrophils also regulate T cell function and, like macrophages, neutrophil function is modulated with aging. It is possible that age-modified tissue-specific macrophages and neutrophils contribute to chronic low-grade inflammation that is associated with dysregulated macrophage-mediated immunosuppression, which together are responsible for development of multiple pathologies, including cancer. This review discusses recent advances in macrophage and neutrophil biology in healthy aging and cancer. [ABSTRACT FROM AUTHOR]

Recent studies have highlighted the heterogeneity of the tumor microenvironment (ME) and the importance of its analysis to the understanding of its impact on clinical outcomes. In this study, we aimed to analyze the intratumoral distribution of macrophages and fibroblasts in breast cancer (BC) based on the morphological diversity of tumor cells (tubular, alveolar, solid, trabecular and discrete structures) and the clinicopathological parameters of the disease. Thirty-six patients with invasive breast carcinoma of no special type were included in the study. The distribution of macrophages and fibroblasts in the MEs of different morphological structures was assessed using laser microdissection-assisted quantitative RT-PCR analysis of marker genes and double immunofluorescence staining for the CD68, RS1, aSMA, and FAP proteins. Gene expression microarrays were used to determine the expression of genes involved in the regulation of macrophage and fibroblast phenotypes in different morphological structures. We found that different macrophage and fibroblast subpopulations were simultaneously observed in the MEs of morphologically distinct structures but that the frequency of their detection and number of cells detected varied significantly among these structures. In particular, macrophages and fibroblasts were more frequently detected in the ME of solid structures and were rarely observed in tubular structures. A high number of CD68 + RS1 + macrophages in the ME of solid structures was found to be associated with an increased frequency of lymph node metastasis in luminal B HER2 − BC. In contrast, in luminal B HER2 + BC, lymph node involvement was related to the high representation of aSMA + FAP + fibroblasts around trabecular structures. Morphologically distinct structures differed in the mechanisms regulating the macrophage and fibroblast phenotypes. The highest number of overexpressed genes controlling macrophage and fibroblast functions was observed in discrete groups of tumor cells, and the lowest number was observed in alveolar and solid structures. Taken together, our findings indicate the heterogeneous distribution of macrophages and fibroblasts in breast tumors and its close relation to the intratumoral morphological diversity of BC and contribution to lymph node metastasis. [ABSTRACT FROM AUTHOR]

Unlike organized lymphoid tissue, the tumor microenvironment (TME) often includes a high proportion of immunosuppressive macrophages. We model the TME by culturing peritoneal cavity (PerC) cells that naturally have a high macrophage to lymphocyte ratio. Prior studies revealed that, following TCR ligation, PerC T cell proliferation is suppressed due to IFNγ-triggered inducible nitric oxide synthase expression. In this study we assessed the ability of PerC B cells to respond to surrogate activating signals in the presence of high numbers of macrophages. Surface IgM (BCR) ligation led to cyclooxygenase-mediated, and TLR-4 ligation to IL10-mediated, suppression of PerC B cell proliferation. In contrast, PerC B cells had a robust response to CD40 ligation, which could overcome the suppression generated by the BCR or TLR-4 response. However, the CD40 response was suppressed by concurrent TCR ligation. These results reveal the challenges of promoting B and T cell responses in macrophage-rich conditions that model the TME. [ABSTRACT FROM AUTHOR]

Macrophages, as a major cellular component in tumor microenvironment, play an important role in tumor progression. However, their roles in modulation of cytotoxic chemotherapy are still not fully understood. Here, we investigated the influence of Lipoplysaccharides (LPS)-stimulated macrophage products (LSMP) on Withaferin A (WA), a natural compound that derived from the medicinal plant Withania somnifera, as an antitumor agent in human breast cancer cells MDA-MB-231 and prostate cancer cells PC-3. Our results revealed that LSMP may enhance WA-induced apoptosis in both cell lines, the underlying mechanisms of which are closely associated with activation of caspase-8, −9 and −3, cleavage of poly ADP-ribose polymerase (PARP), as well as specifically inhibiting the translocation of nuclear factor-κB (NF-κB) and down-regulation of anti-apoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and inhibitor of apoptosis protein (cIAP1/2). These findings demonstrate that macrophages in tumor microenvironment can modulate tumor responses to chemotoxic agents, providing an effective strategy that targets macrophages to enhance the antitumor efficacy of cytotoxic chemotherapy. [ABSTRACT FROM AUTHOR]

Immunotherapy has shown promising treatment effects for a variety of cancers. However, the immune treatment efficiency for solid tumors is limited owing to insufficient infiltration of immune cells into solid tumors. The conversion of tumor-supportive macrophages to tumor-suppressive macrophages, inducing the functional reversal of macrophages, is an effective method and contributes to a subsequent antitumor response. The current challenge in the field is the poor distribution and systemic side effects associated with the use of cytokines. As a solution to this issue, we designed and synthesized microenvironment-responsive nanoparticles (P) with IL-12 payload (IL-12⊂P1). These nanoparticles could promote the systemic administration and release of IL-12 in the tumor microenvironment, and the locally responsive property of IL-12⊂P1 could subsequently re-educate tumor-associated macrophages (TAMs). In particular, our results illustrated the great therapeutic effects derived from the functional conversion of macrophages. Our strategy was to design a microenvironment-responsive material for local macrophage modification to overcome the physiological barrier of solid tumors. The shifting of macrophage phenotypes via IL-12⊂P1 achieved immunomodulation in the microenvironment for cancer therapy, with negligible cytotoxicity. We expect that the functional regulation of TAMs by pH-responsive nanomaterials is a promising therapeutic approach for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Significance: Tumor progression is supported by non-cancerous stromal cells, of which tumor-associated macrophages (TAMs) are prominent constituents. These cells could be considered promising therapeutic targets, but this requires a better understanding of their heterogeneity under the influence of tumor microenvironmental cues and/or ontogenic differences. Recent Advances: The availability of oxygen is an important regulator of the TAM phenotype, as well as of its access to myelopoietic growth factors. Very recent evidence also demonstrated that macrophages can be derived from embryonal precursors or from monocytes post-birth, introducing yet another level of heterogeneity among macrophages. Critical Issues: The relative contribution of ontogenically distinct macrophages to tumor characteristics is, to a large extent, still an open question. In addition, further knowledge on the role of tumor microenvirontal cues that shape TAMs is warranted. Future Directions: More detailed insights into the TAM-regulating factors will provide new opportunities for therapeutic intervention. Interference with the phenotypes of TAM, which are known to be immunosuppressive and to contribute to dysfunctional tumor blood vessels, is anticipated to be beneficial in combination with chemotherapy and/or immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Although anti-angiogenic therapy is widely applied clinically, its efficacy has been less than expected. Screening for regulatory factors and sensitive indicators to define the effectiveness of these drugs is required. Through a retrospective study of clinical data, we found that patients with a higher peripheral monocyte-to-lymphocyte ratio (MLR) obtained less benefit from recombinant human endostatin (rhES, Endostar®), an anti-angiogenic drug, in lung cancer. Because MLR is positively correlated with macrophage count in tumors, this result suggests that macrophages may influence the effectiveness of rhES therapy in lung cancer. Methods: Clinical data from 72 lung cancer patients treated with rhES were collected. Animal study, flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay, Western blot analysis, and transwell migration assays were carried on Lewis lung carcinoma (LLC) cells, bone marrow-derived macrophages, macrophage cell line RAW264.7, and ANA-1 cells. Results: Clinical data showed that compared with the baseline MLR before rhES treatment, patients with progressive disease had higher MLRs than those of patients with partial response. Experimental results showed that more macrophages were recruited in the LLC tumors after rhES treatment and the majority of them displayed an M2-like phenotype. rhES aggravated hypoxia and the inflammatory response in the tumor microenvironment. Hypoxia promoted the expression of CCL2 by endothelial and fibroblast cells, which could induce macrophages recruitment, and increased levels of inflammatory cytokines (interleukin-4 [IL-4], IL-6, and IL-10) skewed macrophage polarization toward the M2-like phenotype. Hypoxia or inflammation cytokine-treated macrophages enhanced the progression of LLC in vitro and in vivo. Conclusion: We found rhES could aggravate hypoxia and the inflammatory response in the tumor microenvironment. These changes were favorable for macrophage accumulation, and skewed their polarization toward the M2-like phenotype which could help LLC to escape from the anti-angiogenic therapy. Thus, these data indicate the accumulation of macrophages in the tumor microenvironment may adversely affect the efficacy of rhES on lung cancer. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) have important roles in the angiogenesis and tumor immunosuppression of various cancers, including esophageal squamous cell carcinomas (ESCCs). To elucidate the roles of TAMs in ESCCs, we compared the gene expression profiles between human peripheral blood monocyte-derived macrophage-like cells (Macrophage_Ls) and Macrophage_Ls stimulated with conditioned medium of the TE series human ESCC cell line (TECM) (TAM_Ls) using cDNA microarray analysis. Among the highly expressed genes in TAM_Ls, we focused on neural cell adhesion molecule (NCAM). NCAM knockdown in TAM_Ls revealed a significant decrease of migration and survival via a suppression of PI3K-Akt and fibroblast growth factor receptor 1 (FGFR1) signaling. Stimulation by TECM up-regulated the level of FGFR1 in Macrophage_Ls. Recombinant human fibroblast growth factor-2 (rhFGF-2) promoted the migration and survival of TAM_Ls and TE-cells through FGFR1 signaling. Our immunohistochemical analysis of 70 surgically resected ESCC samples revealed that the up-regulated FGF-2 in stromal cells, including macrophages, was associated with more aggressive phenotypes and a high number of infiltrating M2 macrophages. These findings may indicate a novel role of NCAM- and FGF-2-mediated FGFR1 signaling in the tumor microenvironment of ESCCs. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO), used to treat anemia in cancer patients, has been reported to accelerate tumor progression and increase mortality. Research of the mechanism for this effect has focused upon EPOR expression by tumor cells. We model the high macrophage to lymphocyte ratio found in tumor microenvironments (TMEs) by culturing peritoneal cavity (PerC) cells that naturally have a high macrophage to T cell ratio. Following TCR ligation, C57BL/6J PerC T cell proliferation is suppressed due to IFNγ-triggered inducible nitric oxide synthase (iNOS) expression. EPO was tested in the PerC culture model and found to increase T cell suppression. This effect could be abrogated by inhibiting iNOS by enzyme inhibition, genetic ablation, or blocking IFNγ signaling. Flow cytometry revealed the EPOR on CD11b + F4/80 + macrophages. These results suggest that EPO could increase T cell suppression in the TME by acting directly on macrophages. [ABSTRACT FROM AUTHOR]

Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti-Ang-2-neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti-colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells. [ABSTRACT FROM AUTHOR]

Macrophages play important roles in cancer microenvironment. Human cytosolic glycyl-tRNA synthetase (GARS1) was previously shown to be secreted via extracellular vesicles (EVs) from macrophages to trigger cancer cell death. However, the effects of GARS1-containing EVs (GARS1-EVs) on macrophages as well as on cancer cells and the working mechanisms of GARS1 in cancer microenvironment are not yet understood. Here we show that GARS1-EVs induce M1 polarization and facilitate phagocytosis of macrophages. GARS1-EVs triggers M1 polarization of macrophage via the specific interaction of the extracellular cadherin subdomains 1-4 of the cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2) with the N-terminal WHEP domain containing peptide region of GARS1, and activates the RAF-MEK-ERK pathway for M1 type cytokine production and phagocytosis. Besides, GARS1 interacted with cadherin 6 (CDH6) of cancer cells via its C-terminal tRNA-binding domain to induce cancer cell death. In vivo model, GARS1-EVs showed potent suppressive activity against tumor initiation via M1 type macrophages. GARS1 displayed on macrophage-secreted extracellular vesicles suppressed tumor growth in dual mode, namely through pro-apoptotic effect on cancer cells and M1 polarization effect on macrophages. Collectively, these results elucidate the unique tumor suppressive activity and mechanism of GARS1-EVs by activating M1 macrophage via CELSR2 as well as by direct killing of cancer cells via CDH6. [ABSTRACT FROM AUTHOR]