Macrophages In Lung Cancer Research Articles

Enhanced angiogenesis of human umbilical vein endothelial cells via THP-1-derived M2c-like macrophages and treatment with proteasome inhibitors 'bortezomib and ixazomib'.

The leading cause of cancer-related death is lung cancer, with metastasis being the most common cause of death. To elucidate the role of macrophages in lung cancer and angiogenesis processes, we established an in vitro co-culture model of A549 or HUVEC with THP-1 cells that polarized to M2c macrophages with hydrocortisone. The proteasome inhibitors bortezomib and ixazomib were investigated for their effects on proliferation, invasion, migration, metastasis, and angiogenesis pathways. The effects of bortezomib and ixazomib on gene expression in gene panels, including crucial genes related to angiogenesis and proteasomes, were investigated after the co-culture model to determine these effects at the molecular level. In conclusion, bortezomib and ixazomib showed antiproliferative effects in both cells, as well as in M2c macrophage co-culture. M2c macrophages also increased invasion in A549 cells and both invasion and migration in HUVEC. mRNA expression upregulation, specifically in the NFKB and VEGF genes, supported the metastatic and angiogenic effects found in A549 and HUVEC with M2c macrophage co-culture. Additionally, bortezomib inhibited the VEGFB pathway in HUVEC and NFKB1 in A549 cells. The significant findings obtained as a result of this study will provide information regarding angiogenesis induced by M2 macrophages.

Research advances in tissue-resident macrophages and monocyte-derived macrophages in lung cancer

Research advances in tissue-resident macrophages and monocyte-derived macrophages in lung cancer

Cutting edges and therapeutic opportunities on tumor-associated macrophages in lung cancer.

Lung cancer is a disease with remarkable heterogeneity. A deep understanding of the tumor microenvironment (TME) offers potential therapeutic strategies against this malignant disease. More and more attention has been paid to the roles of macrophages in the TME. This article briefly summarizes the origin of macrophages, the mutual regulation between anti-tumoral immunity and pro-tumoral statuses derived from macrophage polarization, and the therapeutic opportunities targeting alternately activated macrophages (AAM)-type macrophage polarization. Among them, cellular components including T cells, as well as acellular components represented by IL-4 and IL-13 are key regulators driving the polarization of AAM macrophages. Novel treatments targeting macrophage-associated mechanisms are mainly divided into small molecule inhibitors, monoclonal antibodies, and other therapies to re-acclimate AMM macrophages. Finally, we paid special attention to an immunosuppressive subgroup of macrophages with T cell immunoglobulin and mucin domain-3 (TIM-3) expression. Based on cellular interactions with cancer cells, TIM3+ macrophages facilitate the proliferation and progression of cancer cells, yet this process exposes targets blocking the ligand-receptor recognition. To sum up, this is a systematic review on the mechanism of tumor-associated macrophages (TAM) polarization, therapeutic strategies and the biological functions of Tim-3 positive macrophages that aims to provide new insights into the pathogenesis and treatment of lung cancer.

MARCKS Modulates ER Stress Response and Promotes Pro-Tumor Macrophages in Lung Cancer

MARCKS Modulates ER Stress Response and Promotes Pro-Tumor Macrophages in Lung Cancer

Advances in the Study of Tumor-associated Macrophages in Lung Cancer

肺癌是全球发病率和死亡率最高的恶性肿瘤之一。因此对于肺癌治疗手段的研究也在不断深入，目前临床上主要有全身化疗、针对驱动基因阳性的靶向治疗、免疫检查点抑制剂的应用、抗肿瘤血管生成治疗以及上述不同治疗方法的联合等，这些方案的使用明显改善了大多数肺癌患者的预后，但晚期患者预后仍然不尽如人意。近年来，与免疫相关的肿瘤微环境（tumor microenvironment, TME）的研究越来越受到重视。TME由免疫细胞、成纤维细胞、血管内皮细胞等细胞成分及相关的细胞因子等组成，是肿瘤细胞赖以生存、发展的基础。而肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）是TME重要的免疫细胞，指浸润于肿瘤组织中的巨噬细胞，可促进肿瘤细胞增殖，诱导肿瘤免疫耐受，刺激肿瘤血管生成，增加肿瘤细胞的侵袭及转移能力。因此，靶向TAMs已经成为肺癌免疫治疗的热点。本文就TAMs来源、表型及其在肺癌中的作用机制以及在未来治疗中的靶点进行综述，为肺癌最优化治疗提供参考。

Exosome miR-155-5p Derived from Lung Cancer Hcc827 Promotes Macrophage Activation and Lung Cancer Progression

This stud intends to assess whether exosome miR-155-5p derived from human non-small cell lung cancer cells (Hcc827) activates macrophages in lung cancer. Lung cancer Hcc827 cells were assigned into control group and expeirmental group (cultured with macrophages, THP-1 activated by exosome miR-155-5P derived from Hcc827) followed by analysis of macrophage markers inducible nitric oxide synthase (INOS), recombinant human CD163 (CD163), matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 2 (MMP2), and E-cadherin by real-time fluorescent quantitative PCR (RFQ-PCR), IL-10, IL-6 and IL-8 levels by chemiluminescence, cell invasion by Transwell assay and related protein expression by Western blot. miR-155-5p treatment significantly reduced INOS and TNF-β expressions and increased CD163, TNF-α, IL-8, IL-6 and IL-10 expressions along with enhanced cell invasion. In addition, MMP9 and MMP2 expressions in experimental group were significantly increased and E-cdherin was reduced. In conclusion, exosome miR-155-5p derived from lung cancer Hcc827 cells activates macrophages and enhanced lung cancer cell invasion.

A narrative review of tumor-associated macrophages in lung cancer: regulation of macrophage polarization and therapeutic implications.

Lung cancer is the deadliest malignancy worldwide. An inflammatory microenvironment is a key factor contributing to lung tumor progression. Tumor-Associated Macrophages (TAMs) are prominent components of the cancer immune microenvironment with diverse supportive and inhibitory effects on growth, progression, and metastasis of lung tumors. Two main macrophage phenotypes with different functions have been identified. They include inflammatory or classically activated (M1) and anti-inflammatory or alternatively activated (M2) macrophages. The contrasting functions of TAMs in relation to lung neoplasm progression stem from the presence of TAMs with varying tumor-promoting or anti-tumor activities. This wide spectrum of functions is governed by a network of cytokines and chemokines, cell-cell interactions, and signaling pathways. TAMs are promising therapeutic targets for non-small cell lung cancer (NSCLC) treatment. There are several strategies for TAM targeting and utilizing them for therapeutic purposes including limiting monocyte recruitment and localization through various pathways such as CCL2-CCR2, CSF1-CSF1R, and CXCL12-CXCR4, targeting the activation of TAMs, genetic and epigenetic reprogramming of TAMs to antitumor phenotype, and utilizing TAMs as the carrier for anti-cancer drugs. In this review, we will outline the role of macrophages in the lung cancer initiation and progression, pathways regulating their function in lung cancer microenvironment as well as the role of these immune cells in the development of future therapeutic strategies.

Tumor‑associated macrophages in lung cancer: Friendly or evil? (Review)

Typically, tumor-associated macrophages (TAMs), an abundant population of leukocytes in lung cancer, are affected by tumor microenvironment (TME) and shift towards either a pro-tumor (M2-like) or an anti-tumor phenotype (M1-like). M2-polarized macrophages, are one of the primary tumor-infiltrating immune cells and were reported to be associated with the promotion of cancer cell growth, invasion, metastasis, and angiogenesis. TAMs are considered a potential target for adjuvant anticancer therapies, and recent therapeutic approaches targeting the M2 polarization of TAMs have shown encouraging results. The present review discusses recent developments in the role of TAMs in cancer, in particular TAMs functions, clinical implication and prospective therapeutic strategies in lung cancer.

Oct4 promotes M2 macrophage polarization through upregulation of macrophage colony-stimulating factor in lung cancer

BackgroundExpression of Oct4 maintains cancer stem cell (CSC)-like properties in lung cancer cells and is correlated with poor prognosis of lung adenocarcinoma. M2-type tumor-associated macrophages (TAMs) promote cancer cell migration and metastasis. Tumor microenvironments promote monocyte differentiation into M2 TAMs via a complex cytokine-based connection. We explored the role of Oct4 in cytokine secretion in lung cancer and its impact on M2 TAM polarization.MethodsMonocytes co-cultured with the conditioned medium from Oct4-overexpressing lung cancer cells were used to investigate M2 TAM differentiation. The inflammatory factors in the conditioned medium of Oct4-overexpressing A549 cells were examined using human inflammation antibody arrays. The correlations of Oct4, macrophage colony-stimulating factor (M-CSF), and M2 TAMs were validated in lung cancer cells, syngeneic mouse lung tumor models, and clinical samples of non-small cell lung cancer (NSCLC).ResultsOct4-overexpressing A549 cells expressed elevated levels of M-CSF, which contributed to increased M2 macrophages and enhanced tumor migration. Overexpression of Oct4 enhanced tumor growth and reduced the survival of lung tumor-bearing mice, which was correlated with increased number of M2 macrophages in lung cancer. Notably, NSCLC patients with high expression levels of Oct4, M-CSF, and M2 TAMs had the poorest recurrence-free survival. A positive correlation between Oct4, M-CSF, and M2 TAMs was observed in the tumor tissue of NSCLC patient. Treatment with all-trans retinoic acid exerted anti-tumor effects and reduced M2 TAMs in tumor-bearing mice.ConclusionsOur results indicate that Oct4 expressed by lung cancer cells promotes M2 macrophage polarization through upregulation of M-CSF secretion, leading to cancer growth and metastasis. Our findings also implicate that the Oct4/M-CSF axis in M2 macrophage polarization may be potential therapeutic targets for lung cancer.

Transcription factor c-Maf is a checkpoint that programs macrophages in lung cancer.

Macrophages have been linked to tumor initiation, progression, metastasis, and treatment resistance. However, the transcriptional regulation of macrophages driving the protumor function remains elusive. Here, we demonstrate that the transcription factor c-Maf is a critical controller for immunosuppressive macrophage polarization and function in cancer. c-Maf controls many M2-related genes and has direct binding sites within a conserved noncoding sequence of the Csf-1r gene and promotes M2-like macrophage-mediated T cell suppression and tumor progression. c-Maf also serves as a metabolic checkpoint regulating the TCA cycle and UDP-GlcNAc biosynthesis, thus promoting M2-like macrophage polarization and activation. Additionally, c-Maf is highly expressed in tumor-associated macrophages (TAMs) and regulates TAM immunosuppressive function. Deletion of c-Maf specifically in myeloid cells results in reduced tumor burden with enhanced antitumor T cell immunity. Inhibition of c-Maf partly overcomes resistance to anti-PD-1 therapy in a subcutaneous LLC tumor model. Similarly, c-Maf is expressed in human M2 and tumor-infiltrating macrophages/monocytes as well as circulating monocytes of human non-small cell lung carcinoma (NSCLC) patients and critically regulates their immunosuppressive activity. The natural compound β-glucan downregulates c-Maf expression on macrophages, leading to enhanced antitumor immunity in mice. These findings establish a paradigm for immunosuppressive macrophage polarization and transcriptional regulation by c-Maf and suggest that c-Maf is a potential target for effective tumor immunotherapy.

Targeting folate receptor \u03b2 positive tumor-associated macrophages in lung cancer with a folate-modified liposomal complex

Tumor-associated macrophages (TAMs) facilitate cancer progression by promoting tumor invasion, angiogenesis, metastasis, inflammatory responses, and immunosuppression. Folate receptor β (FRβ) is overexpressed in TAMs. However, the clinical significance of FRβ-positive macrophages in lung cancer remains poorly understood. In this study, we verified that FRβ overexpression in lung cancer TAMs was associated with poor prognosis. We utilized a folate-modified lipoplex comprising a folate-modified liposome (F-PLP) delivering a BIM-S plasmid to target both lung cancer cells and FRβ-positive macrophages in the tumor microenvironment. Transfection of LL/2 cells and MH-S cells with F-PLP/pBIM induced cell apoptosis. Injection of F-PLP/pBIM into LL/2 and A549 lung cancer models significantly depleted FRβ-positive macrophages and reduced tumor growth. Treatment of tumor-bearing mice with F-PLP/pBIM significantly inhibited tumor growth in vivo by inducing tumor cell and macrophage apoptosis, reducing tumor proliferation, and inhibiting tumor angiogenesis. In addition, a preliminary safety evaluation demonstrated a good safety profile of F-PLP/pBIM as a gene therapy administered intravenously. This work describes a novel application of lipoplexes in lung cancer targeted therapy that influences the tumor microenvironment by targeting TAMs.

USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer.

Background: Tumor associated macrophages (TAMs) have strong plasticity and if reprogrammed, can clear tumor cells and regulate the adaptive immune system for cancer immunotherapy. Deubiquitinating enzymes (DUBs), which can remove ubiquitin (Ub) from Ub-modified substrates, have been associated with oncogenic metabolism but are not well-known for regulating TAMs repolarization.Methods: The expression of DUB related genes in macrophages (MΦs) was detected by reverse transcription-PCR. Flow cytometry and immunofluorescence were used to detect the changes of immune cells in the tumor microenvironment and spleen, including M1 (CD11b+F4/80+CD86+CD206-), and M2 (CD11b+F4/80+CD86-CD206+) MΦs, and IFN-γ+CD8+T cells. A proliferation assay was used to determine the effect of M2 MΦs treated with a USP7 inhibitor on T cell proliferation. Western blotting was used to detect the expression of USP7 and the activation of the MAPK pathway. The TGCA database was used to assess the role of USP7 in the immune microenvironment of human lung adenocarcinoma (LUAD).Results: 51 DUB genes were screened and USP7 was identified as a highly expressed gene in M2 but not M1 MΦs. Specific silencing of USP7 using siRNA or USP7 inhibitors led to phenotypical and functional changes in M2 MΦs, favoring CD8+T cells proliferation in vitro. USP7 inhibitors delayed tumor growth in mice with Lewis lung carcinoma, and promoted tumor infiltration of M1 MΦs and IFN-γ+CD8+T cells. Depletion of TAMs attenuated these therapeutic effects. USP7 inhibition was shown to mediate MΦs reprogramming by activating the p38 MAPK pathway. Administration of USP7 inhibitors increased the expression of programmed cell death ligand 1 (PD-L1) in tumors, while blocking programmed cell death protein 1 (PD-1) provided an effective anti-tumor response. Clinical databases suggest that high expression of USP7 in LUAD was negatively correlated with innate and adaptive immunity.Conclusions: Taken together, these results provide evidence to suggest that therapeutic approaches targeting USP7, in combination with immunotherapy, should be considered for lung cancer treatment.

Catecholamines contribute to the neovascularization of lung cancer via tumor-associated macrophages

PurposeElevated catecholamines in the tumor microenvironment often correlate with tumor development. However, the mechanisms by which catecholamines modulate lung cancer growth are still poorly understood. This study is aimed at examining the functions and mechanisms of catecholamine-induced macrophage polarization in angiogenesis and tumor development. Experimental designWe established in vitro and in vivo models to investigate the relationship between catecholamines and macrophages in lung cancer. Flow cytometry, cytokine detection, tube formation assay, immunofluorescence, and western blot analysis were performed, and animal models were also used to explore the underlying mechanism of catecholamine-induced macrophage polarization and host immunological response. ResultsCatecholamines were shown to be secreted into tumor under the control of the sympathetic nerve system to maintain the pro-tumoral microenvironment. In vivo, the chemical depletion of the natural catecholamine stock with 6OHDA could reduce the release of catecholamines within tumor tissues, restrain the function of alternatively activated M2 macrophage, attenuate tumor neovascularization, and inhibit tumor growth. In vitro, catecholamine treatment triggered the M2 polarization of macrophages, enhanced the expression of VEGF, promoted tumor angiogenesis, and these catecholamine-stimulated effects could be reversed by the adrenergic receptor antagonist propranolol. In addition to regulating tumor-associated macrophages (TAM) recruitment, decreasing catecholamine levels could also shift the immunosuppressive microenvironment by decreasing myeloid-derived suppressor cells’ (MDSCs) recruitment and facilitating dendritic cells’ (DCs) activation, potentially resulting in a positive antitumor immune response. ConclusionOur study demonstrates the potential of adrenergic stress and catecholamine-driven adrenergic signaling of TAMs to regulate the immune status of a tumor microenvironment and provides promising targets for anticancer therapies.

Abstract 4636: p53 governs the tumoricidal activity of M1 macrophages in lung cancer

Abstract Macrophages in a tumor microenvironment have been characterized as M1- and M2-polarized subtypes. M1 macrophage is associated with favorable clinical outcome of lung cancer patients, but the detail molecular mechanism is not thoroughly understood. Herein, we elucidate the anti-tumor mechanism of M1 macrophages by in vitro and in vivo assays. M1 conditioned media (CM) significantly reduced the tumor size in the xenograft mouse model via intratumoral administration. The M1-altered differential expression was profiled by microarray and the pathway analysis indicated that p53 was a critical regulator. Lung cancer cells harboring wild-type p53 (wt-p53) went apoptosis after M1 CM culture, but cells with mutant p53 did not. Additionally, M1 CM enhanced wt-p53 accumulation through reducing p53 ubiquitination and increasing protein stability. Moreover, we identified a p53 interacting protein STAT1 involved in M1-induced apoptosis and p53 accumulation. The M1 CM not only enhanced the interaction between STAT1 and p53 but also up-regulated and activated STAT1. We found that STAT1-Y701 phosphorylation is required for the p53 stability. The interaction of STAT1-Y701F and p53 was reduced compared to wild-type STAT1. To reveal the upstream signaling, we found that knockdown of IFNAR2, JAK1 and TYK2 attenuates M1-induced apoptosis. Taken together, STAT1 signaling is essential for M1 CM-induced apoptosis and p53 accumulation. Our findings imply that p53 and M1 macrophages play important roles in the immune surveillance in lung cancers. Citation Format: Yi-Jing Hsiao, Hsuan-Yu Chen, Kang-Yi Su, Bing-Ching Ho, Jeremy J.W. Chen, Pan-Chyr Yang, Sung-Liang Yu. p53 governs the tumoricidal activity of M1 macrophages in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4636. doi:10.1158/1538-7445.AM2017-4636

β-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer

Macrophages in tumor are mostly M2-polarized and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). β-elemene has therapeutic effects against several cancers, however, it remains unknown whether β-elemene could inhibit cancer by targeting TAMs. Herein, we examined the effect of β-elemene on macrophages to elucidate a novel mechanism of β-elemene in tumor therapy. We showed that the conditioned medium of M2 macrophages promoted lung cancer cells to migration, invasion and epithelial mesenchymal transition, which could be inhibited by β-elemene. Moreover, β-elemene regulated the polarization of macrophages from M2 to M1. β-elemene also inhibited the proliferation, migration, invasion of lung cancer cells and enhanced its radiosensitivity. These results indicate β-elemene suppresses lung cancer by regulating both macrophages and lung cancer cells, it is a promising drug for combination with chemotherapy or radiotherapy.

Systemic and Tumor Th1 and Th2 Inflammatory Profile and Macrophages in Lung Cancer: Influence of Underlying Chronic Respiratory Disease

IntroductionChronic respiratory conditions, especially chronic obstructive pulmonary disease (COPD), and inflammatory events underlie lung cancer (LC). We hypothesized that profiles of T helper 1 and T helper 2 cytokines and type 1 and type 2 macrophages (M1 and M2) are differentially expressed in lung tumors and blood of patients with NSCLC with and without COPD and that the ratio M1/M2 specifically may influence their survival. MethodsIn blood, inflammatory cytokines (determined by enzyme-linked immunosorbent assay) were quantified in 80 patients with LC (60 with LC and COPD [the LC-COPD group] and 20 with LC only [the LC-only group]) and lung specimens (tumor and nontumor) from those undergoing thoracotomy (20 in the LC-COPD group and 20 in the LC-only group). ResultsIn the LC-COPD group compared with in the LC-only group, systemic levels of tumor necrosis factor-α, interleukin-2 (IL-2), transforming growth factor-β, and IL-10 were increased, whereas vascular endothelial growth factor and IL-4 levels were decreased. In lung tumors, levels of tumor necrosis factor-α, transforming growth factor-β, and IL-10 were higher than in nontumor parenchyma in the LC-COPD group, whereas IL-2 and vascular endothelial growth factor levels were higher in tumors of both the LC-only and LC-COPD groups. Compared with in nontumor lung, M1 macrophage counts were reduced whereas M2 counts were increased in tumors of both patient groups, and the M1/M2 ratio was higher in the LC-COPD group than the LC-only group. M1 and M2 counts did not influence patients’ survival. ConclusionsThe relative predominance of T helper 1 cytokines and M1 macrophages in the blood and tumors of patients with underlying COPD imply that a stronger proinflammatory pattern exists in these patients. Inflammation should not be targeted systematically in all patients with LC. Screening for the presence of underlying respiratory diseases and identification of the specific inflammatory pattern should be carried out in patients with LC, at least in early stages of their disease.

Abstract 4157: IL-6 glycoforms differentially modulate the polarization of tumor-associated macrophages in lung cancer

Abstract Interleukin-6 (IL-6) is critical in modulating both tumor growth and anti-tumor immunity. Here, we describe the glycosylation pattern of lung cancer cell-secreted IL-6 and examine the function of the IL-6 glycoforms in polarization of tumor-associated macrophages (TAMs). IL-6 with different molecular weights were detected in various lung cancer cells. Because in NetNGlyc 1.0 Server, one possible N-glycosylation site has been predicted at N73 on IL-6, we used tunicamycin treatment and site-directed mutagenesis on N73 to demonstrate that lung cancer cell-secreted IL-6 is modified by N-glycosylation. To explore more detailed attached glycans, we measured the expression of glycosyltransferases by qPCR and found that the expression of fucosyltransferase 8 (FUT8), responsible for core fucosylation on N-glycosylated proteins, was higher in lung cancer cells than normal bronchial cells. Core fucosylation on IL-6 was reduced by silencing FUT8. We generated AS2-IL6, AS2-IL6-shFUT8, and AS2-IL6-N73Q cells for producing full-glycosylated IL-6 (G-IL6), core fucose-depleted IL-6 (DeCF-IL6), and Asn73-N-glycan-depleted IL-6 (N73Q-IL6). To examine the effect of the IL-6 glycoforms on differentiation of TAMs, THP-1 monocytic leukemic cells were incubated with phorbol-12-myristate 13-acetate for transforming to macrophages, followed by co-culture with the AS2 cell derivatives to mimic the education of TAMs. The co-cultured TAMs of each AS2 derivative showed distinct morphology. Intriguingly, the G-IL6-producing cells promote the expression of M2-TAM markers CD204, CCR1, arginase-1, and M2-specific cytokines that benefit anti-tumor activity, while DeCF-IL6 and N73Q-IL6 favored the formation of M1 macrophages. The phagocytosis capacity of cocultured macrophages is also altered by different IL-6 glycoform-secreting cells. On the other hand, the Stat3 activation status induced by IL-6 glycoforms is concordant to our previous results, in which the G-IL6 can induce a persistant Stat3 activation that is not observed in the DeCF-IL6- and N73Q-IL6-induced macrophages. We subsequently examined the distribution and polarization of TAMs in in vivo xenograft tumor model by both subcutaneous and intravenous injection of the IL-6 glycoform-overexpressing cells. Higher proportion of M2 TAM was attracted by the N73Q-IL6 tumor than other glycoform tumors. Together, we report the presence of specific IL-6 glycoforms secreted from lung cancer cells. Moreover, the glycosylation on IL-6 changes its activity on the polarization of TAMs, suggesting the pivotal role of soluble factor(s) in orchestrating the tumor microenvironment of lung cancer. Citation Format: Chun-Hua Hung, Hao-Chen Wang, Hsuan-Heng Yeh, Chien-Chung Lin, Wu-Chou Su. IL-6 glycoforms differentially modulate the polarization of tumor-associated macrophages in lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4157.

TREM-1low is a novel characteristic for tumor-associated macrophages in lung cancer.

ObjectiveTo explore the expression feature and biological functions of TREM-1 on tumor-associated macrophages (TAMs) in lung cancer.ResultsThe levels of TREM-1 on tissue-infiltrating monocytes/macrophage from tumor nest were significantly lower than those from nonturmor tissue or peripheral blood samples. Clinical analysis indicated that the levels of TREM-1-related TAMs were significantly decreased during cancer stages progression. The tumor-bearing mouse model further confirmed that the expression of TREM-1 on TAMs was significantly decreased with tumor growth. In addition, we found the activation of TREM-1 could significantly enhance the secretion of IL-1β by TAM in vitro. Furthermore, T-bet but not Eomes was found to be the key transcription factor for the TREM-1 expression on monocytes/macrophage.MethodsA total of 40 patients with non-small cell lung cancer (NSCLC) were enrolled in this study. The expression characteristics of TREM-1 in blood and tissue-infiltrating monocytes/macrophage were examined by flow cytometry analysis. After the treatment of TREM-1 antibody, which is an agonist of TREM-1, cytokines secreted by TAM were then analyzed. In LLC-tumor bearing mouse model, we further investigated the dynamic expression feature of TREM-1 on macrophage with tumor growth. Moreover, we explored the transcription factor for regulating TREM-1 expression on monocyes/macrophage with wildtype, T-bet Ko or Eomes Ko mice.ConclusionThe levels of TREM-1 were remarkably decreased during tumor progression. The low expression level of TREM-1 might be a characteristic for TAMs in lung cancer.

Clinical significance of PD-L1 protein expression on tumor-associated macrophages in lung cancer

Tumor PD-L1 expression is associated with increased tumor-infiltrating lymphocytes (TILs) in diverse solid tumors, including lung cancer. In addition, PD-L1 upregulation in tumor and/or stromal immune cells has been associated with increased clinical benefit to PD-1/PD-L1 axis blockers. The significance of PD-L1 expression in different immune cell subpopulations at the tumor microenvironment remains poorly understood. Here, we measured PD-L1 protein specifically in tumor-associated macrophages using objective methods and analyzed its clinical significance in human lung cancer.

Alveolar Macrophage Polarisation in Lung Cancer.

The role of alveolar macrophages in lung cancer is multifaceted and conflicting. Alveolar macrophage secretion of proinflammatory cytokines has been found to enhance antitumour functions, cytostasis (inhibition of tumour growth), and cytotoxicity (macrophage-mediated killing). In contrast, protumour functions of alveolar macrophages in lung cancer have also been indicated. Inhibition of antitumour function via secretion of the anti-inflammatory cytokine IL-10 as well as reduced secretion of proinflammatory cytokines and reduction of mannose receptor expression on alveolar macrophages may contribute to lung cancer progression and metastasis. Alveolar macrophages have also been found to contribute to angiogenesis and tumour growth via the secretion of IL-8 and VEGF. This paper reviews the evidence for a dual role of alveolar macrophages in lung cancer progression.