Tumor-associated Macrophages Subtype Research Articles

Tumor-associated macrophage subtypes on cancer immunity along with prognostic analysis and SPP1-mediated interactions between tumor cells and macrophages.

Tumor-associated macrophages (TAM) subtypes have been shown to impact cancer prognosis and resistance to immunotherapy. However, there is still a lack of systematic investigation into their molecular characteristics and clinical relevance in different cancer types. Single-cell RNA sequencing data from three different tumor types were used to cluster and type macrophages. Functional analysis and communication of TAM subpopulations were performed by Gene Ontology-Biological Process and CellChat respectively. Differential expression of characteristic genes in subpopulations was calculated using zscore as well as edgeR and Wilcoxon rank sum tests, and subsequently gene enrichment analysis of characteristic genes and anti-PD-1 resistance was performed by the REACTOME database. We revealed the heterogeneity of TAM, and identified eleven subtypes and their impact on prognosis. These subtypes expressed different molecular functions respectively, such as being involved in T cell activation, apoptosis and differentiation, or regulating viral bioprocesses or responses to viruses. The SPP1 pathway was identified as a critical mediator of communication between TAM subpopulations, as well as between TAM and epithelial cells. Macrophages with high expression of SPP1 resulted in poorer survival. By in vitro study, we showed SPP1 mediated the interactions between TAM clusters and between TAM and tumor cells. SPP1 promoted the tumor-promoting ability of TAM, and increased PDL1 expression and stemness of tumor cells. Inhibition of SPP1 attenuated N-cadherin and β-catenin expression and the activation of AKT and STAT3 pathway in tumor cells. Additionally, we found that several subpopulations could decrease the sensitivity of anti-PD-1 therapy in melanoma. SPP1 signal was a critical pathway of communication between macrophage subtypes. Some specific macrophage subtypes were associated with immunotherapy resistance and prognosis in some cancer types.

The heterogeneity of tumour-associated macrophages contributes to the clinical outcomes and indications for immune checkpoint blockade in colorectal cancer patients

Tumor-associated macrophages (TAMs), one of the major immune cell types in colorectal cancer (CRC) tumor microenvironment (TME), play indispensable roles in immune responses against tumor progression. In this study, we aimed to know whether the extensive inter and intra heterogeneity of TAMs contributes to the clinical outcomes and indications for immune checkpoint blockade (ICB) in CRC. We used single-cell RNA sequencing (scRNA-Seq) data from 60 CRC patients and charactrized TAMs based on anatomic locations, tumor regions, stages, grades, metastatic status, MSS/MSI classification and pseudotemporal differentiation status. We then defined a catalog of 21 gene modules that determine macrophage status, and identified 7 of them as relevant to clinical outcomes and 11 as indications for ICB therapy. On this basis, we constructed a unique TAM subgroup profile, aiming to find features that may be highly responsive to immunotherapy for the CRC with poor prognosis under conventional treatment. This TAM subpopulation is enriched in tumors and is associated with poor prognosis, but exhibits a high immunotherapy response signature (HIM TAM). Further spatial transcriptome analysis and ligand-receptor interaction analysis confirmed that HIM TAM is involved in shaping TIME, especially the regulation of T cells. Our study provides insights into different TAM subtypes, highlights the importance of TAM heterogeneity in relation to patient prognosis and immunotherapy response, and reveals potential immunotherapy strategies based on TAM characteristics for CRC that does not respond well to conventional therapy.

Riboflavin-LSD1 axis participates in the in vivo tumor-associated macrophage morphology in human colorectal liver metastases

Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME). In colorectal liver metastasis (CLM), TAM morphology correlates with prognosis, with smaller TAMs (S-TAMs) conferring a more favorable prognosis than larger TAMs (L-TAMs). However, the metabolic profile of in vivo human TAM populations remains unknown. Multiparametric flow cytometry was used to freshly isolate S- and L-TAMs from surgically resected CLM patients (n = 14S-, 14L-TAMs). Mass spectrometry-based metabolomics analyses were implemented for the metabolic characterization of TAM populations. Gene expression analysis and protein activity were used to support the biochemical effects of the enzyme–substrate link between riboflavin and (lysine-specific demethylase 1A, LSD1) with TAM morphologies. L-TAMs were characterized by a positive correlation and a strong association between riboflavin and TAM morphologies. Riboflavin in both L-TAMs and in-vitro M2 polarized macrophages modulates LSD1 protein expression and activity. The inflammatory stimuli promoted by TNFα induced the increased expression of riboflavin transporter SLC52A3 and LSD1 in M2 macrophages. The modulation of the riboflavin-LSD1 axis represents a potential target for reprogramming TAM subtypes, paving the way for promising anti-tumor therapeutic strategies.

Single-cell analysis reveals diversity of tumor-associated macrophages and their interactions with T lymphocytes in glioblastoma

Glioblastoma (GBM) is an aggressive primary CNS malignancy and clinical outcomes have remained stagnant despite introduction of new treatments. Understanding the tumor microenvironment (TME) in which tumor associated macrophages (TAMs) interact with T cells has been of great interest. Although previous studies examining TAMs in GBM have shown that certain TAMs are associated with specific clinical and/or pathologic features, these studies used an outdated M1/M2 paradigm of macrophage polarization and failed to include the continuum of TAM states in GBM. Perhaps most significantly, the interactions of TAMs with T cells have yet to be fully explored. Our study uses single-cell RNA sequencing data from adult IDH-wildtype GBM, with the primary aim of deciphering the cellular interactions of the 7 TAM subtypes with T cells in the GBM TME. Furthermore, the interactions discovered herein are compared to IDH-mutant astrocytoma, allowing for focus on the cellular ecosystem unique to GBM. The resulting ligand-receptor interactions, signaling sources, and global communication patterns discovered provide a framework for future studies to explore methods of leveraging the immune system for treating GBM.

Cellular crosstalk of macrophages and therapeutic implications in non-small cell lung cancer revealed by integrative inference of single-cell transcriptomics.

Introduction: Non-small cell lung cancer (NSCLC) exhibits heterogeneity with diverse immune cell infiltration patterns that can influence tumor cell behavior and immunotherapy. A comprehensive characterization of the tumor microenvironment can guide precision medicine. Methods: Here, we generated a single-cell atlas of 398170 cells from 52 NSCLC patients, and investigated the imprinted genes and cellular crosstalk for macrophages. Subsequently, we evaluated the effect of tumor cells on macrophages and verified the expression of marker genes using co-culture experiments, flow cytometry and RT-qPCR assays. Results: Remarkable macrophage adaptability to NSCLC environment was observed, which contributed to generating tumor-associated macrophages (TAMs). We identified 5 distinct functional TAM subtypes, of which the majority were SELENOP-positive macrophages, with high levels of SLC40A1 and CCL13. The TAMs were also involved in mediating CD8+ T cell activity and form intercellular interaction with cancer cells, as indicated by receptor-ligand binding. Indirect coculture of tumor cells SPC-A1 and THP-1 monocytes, produced M2-like TAMs that highly expressed several markers of SELENOP-positive macrophages. The abundance of this type TAMs seemed to be associated with poorer overall survival rates [hazard ratio (HR) = 1.34, 95% confidence interval (CI) = 0.98-1.83, p = 0.068] based on deconvolution of TCGA-LUAD dataset. Discussion: In summary, we provided a high-resolution molecular resource of TAMs, and displayed the acquired properties in the tumor microenvironment. Dynamic crosstalk between TAMs and tumor cells via multiple ligand-receptor pairs were revealed, emphasizing its role in sustaining the pro-tumoral microenvironment and its implications for cancer therapy.

Glycolysis regulation in tumor-associated macrophages: Its role in tumor development and cancer treatment.

Tumor-associated macrophages constitute the main cell population in the tumor microenvironment and play a crucial role in regulating the microenvironment composition. Emerging evidence has revealed that the metabolic profile determines the tumor-associated macrophage phenotype. Tumor-associated macrophage function is highly dependent on glucose metabolism, with glycolysis being the major metabolic pathway. Recent reports have demonstrated diversity in glucose flux of tumor-associated macrophages and complex substance communication with cancer cells. However, how the glucose flux in tumor-associated macrophages connects with glycolysis to influence tumor progression and the tumor microenvironment is still obscure. Moreover, while the development of single-cell sequencing technology allows a clearer and more accurate classification of tumor-associated macrophages, the metabolic profiles of tumor-associated macrophages from the perspective of single-cell omics has not been well summarized. Here, we review the current state of knowledge on glucose metabolism in tumor-associated macrophages and summarize the metabolic profiles of different tumor-associated macrophage subtypes from the perspective of single-cell omics. Additionally, we describe the current strategies targeting glycolysis in tumor-associated macrophages for cancer therapy.

Targeting reactive oxygen species and fat acid oxidation for the modulation of tumor-associated macrophages: a narrative review.

Tumor-associated macrophages (TAMs) are significant immunocytes infiltrating the tumor microenvironment(TME). Recent research has shown that TAMs exhibit diversity in terms of their phenotype, function, time, and spatial distribution, which allows for further classification of TAM subtypes. The metabolic efficiency of fatty acid oxidation (FAO) varies among TAM subtypes. FAO is closely linked to the production of reactive oxygen species (ROS), which play a role in processes such as oxidative stress. Current evidence demonstrates that FAO and ROS can influence TAMs' recruitment, polarization, and phagocytosis ability either individually or in combination, thereby impacting tumor progression. But the specific mechanisms associated with these relationships still require further investigation. We will review the current status of research on the relationship between TAMs and tumor development from three aspects: ROS and TAMs, FAO and TAMs, and the interconnectedness of FAO, ROS, and TAMs.

Abstract 4653: Spatial architecture of tumor-infiltrating macrophagesorchestrates tumor immunity and therapeutic response

Abstract Tumor-infiltrating macrophages, a major cellular component in the tumor microenvironment (TME), have been proven to be linked with tumor progression and immunotherapy resistance. Tremendous heterogeneity has been revealed for tumor-associated macrophages (TAMs) in different cancer types, however, how these TAM subtypes are localized and interact with tissue ecosystems remains poorly understood. Here, we perform an integrative analysis of TAMs, malignant and non-malignant cells from 10 cancer types, based on single-cell RNA-seq and spatial transcriptomic data. By interrogating the spatial distributions of different TAM subtypes in situ, we reveal spatially restricted developmental, regulation, and functional heterogeneity of TAMs in TME. Different cancer types show distinct TAM subtype enrichments with specific interface architectures, which is potentially shaped by the cellular compositions and spatial niches of tumor cells. Furthermore, the compartmentalized TAM subpopulations can reflect the spatial architecture of surrounding stromal and immune cells, and thus orchestrate tumor immunity and therapeutic response. Our study demonstrates the cellular and molecular underpinnings of TAM heterogeneity and stochastic regulations of TAMs for TME architecture, tumor progression and immunotherapy responses, which will assist in the identification of possible therapeutic targets. Citation Format: Yuanyuan Zhang, Fuduan Peng, Guangsheng Pei, Yunhe Liu, Guangchun Han, Linghua Wang. Spatial architecture of tumor-infiltrating macrophagesorchestrates tumor immunity and therapeutic response. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4653.

The role of NFATc1/c-myc/PKM2/IL-10 axis in activating cervical cancer tumor-associated M2 macrophage polarization to promote cervical cancer progression

Nuclear factor of activated T cells 1 (NFATc1) is mainly expressed in tumor microenvironment, especially in macrophages. However, whether NFATc1 is involved in the polarization of tumor associated macrophages (TAMs) and tumor progression in cervical cancer (CC) remains unclear. Immunofluorescence staining was used to detect the expression of CD68 and NFATc1 in CC tissues or adjacent normal tissues of patients. RT-qPCR, flow cytometry, ELISA, and inhibitors treatment were used to observe the effect of NFATc1 on TAMs polarization. Clonal formation, scratch, and transwell assays were used to examine the effects of NFATc1-transfected macrophages or NFATc1-transfected TAM on tumor proliferation, migration, and invasion. Further, a xenograft model was established to confirm the roles of NFATc1+ TAM in CC tumorigenesis. NFATc1+CD68+/CD68+ TAMs ratio was significantly increased in CC tissues compared with the normal tissue, and NFATc1+ TAM showed an M2-like TAM subtype. NFATc1 induced macrophages to secrete IL-10, which further induced M2 polarization of macrophages. Mechanically, the c-myc-PKM2 pathway mediated the expression of IL-10 in NFATc1-induced macrophages. Functionally, NFATc1 induced M2 macrophages promoted the proliferation, migration, and invasion of CC cells, and the knockout of NFATc1 in TAMs significantly inhibited the tumor-promoting function of TAMs. Further, the tumorigenesis test in nude mice confirmed that NFATc1+ TAM promoted the tumorigenicity of CC cells in vivo. In conclusion, NFATc1 mediated IL-10 secretion by regulating the c-myc/PKM2 pathway, thereby inducing M2 polarization of TAMs and promoting the progression of CC.

C-Reactive Protein Is an Indicator of the Immunosuppressive Microenvironment Fostered by Myeloid Cells in Hepatocellular Carcinoma.

BackgroundC-reactive protein (CRP) is a widely used marker of systemic inflammation and predicts poor clinical outcomes in patients with hepatocellular carcinoma (HCC); however, its significance in the local immune response at the tumor site is not clear.MethodsSerum CRP levels of 329 HCC patients were detected before resection. Paired paraffin-embedded tumor samples were used to quantify immune cell populations, such as CD11b+ myeloid cells, CD68+ macrophages (Mφs), CD15+ neutrophils, CD8+ T cells, and CD206+, CD204+, CD163+ and CD169+ Mφs, by immunohistochemistry. Enrichment scores for 34 types of immune cells based on transcriptome data from 24 HCC samples were calculated by xCell. Overall survival of patients was analyzed using the Kaplan-Meier method.ResultsSerum CRP levels were correlated with liver functions and tumor stages in patients with HCC. The densities of CD68+ tumor-associated macrophages (TAMs) and CD15+ tumor-associated neutrophils (TANs) were significantly higher in patients with elevated serum CRP levels than in those with low CRP levels (both p < 0.0001). Further analysis of TAM subtypes revealed that serum CRP levels were associated with CD204+ and CD163+ Mφ densities (p < 0.0001 and p = 0.0003, respectively). Moreover, transcriptome data showed that CRP expression was associated with the expression of myeloid cell infiltration-related genes in HCC tumors. The combination of serum CRP with TAMs or TANs in both the nontumor and intratumor regions could represent a powerful criterion for predicting patient prognoses.ConclusionSerum CRP could serve as an indicator of an immunosuppressive TME in HCC, which could be of potential clinical application for treatment strategies targeting the TME.

Prognostic Significance of Tumor-Associated Macrophages in Chondroblastoma and Their Association with Response to Adjuvant Radiotherapy.

ObjectiveChondroblastoma (CB) is a rare and locally growing cartilage-derived tumor. Currently, clinical implications of tumor-associated macrophages (TAMs) in CB remain unclear. In this study, we sought to analyze the relationship between TAM parameters (including densities of CD68+ and CD163+ cells as well as the CD163+/CD68+ ratio) and clinicopathological characteristics and survival of patients.MethodsImmunohistochemistry was used to assess TAM subtypes for CD68 and CD163, as well as the expression levels of p53, CD34, and Ki-67 on tumor cells in 132 tissue specimens retrieved between July 2002 and April 2020. Then, TAM parameters were retrospectively analyzed for their associations with patient outcomes (local recurrence-free survival [LRFS] and overall survival [OS]) and clinicopathological features.ResultsTAM densities were significantly higher in axial chondroblastoma tissue than in extra-axial chondroblastoma tissue. Moreover, the number of CD163+ TAMs was positively correlated with tumor invasion of surrounding tissues and high expression of CD34 and Ki-67 on tumor cells, whereas CD163+ cell density and the CD163/CD68 ratio were negatively associated with patient response to adjuvant radiotherapy. Univariate Kaplan–Meier analysis revealed that the number of CD68+ and CD163+ lymphocytes was significantly associated with both LRFS and OS. Multivariate Cox regression analysis showed that CD163+ and CD68+ cell levels were independent prognostic factors of LRFS, while TAM data independently predicted OS. More importantly, in subgroup analysis based on three significant factors in univariate survival analysis (including tumor location, adjuvant radiotherapy, and surrounding tissue invasion by tumors), the TAM parameters still displayed good prognostic performance.ConclusionThese data suggest that TAM may significantly affect the biological behavior of CB. We hypothesize that modulating the TAM level or polarization status in the microenvironment may be an effective approach for CB treatment.

Alteration of tumor-associated macrophage subtypes mediated by KRT6A in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is severely affecting the health and lives of patients. Clarifying the composition and regulatory factors of tumor immune microenvironment (TIME) is helpful for the treatment of PDAC. We analyzed the unique TIMEs and gene expression patterns between PDAC and adjacent normal tissue (ANT) using Gene Expression Omnibus (GEO) to find new immunotherapy targets. The Cancer Genome Atlas (TCGA) datasets were used to elucidate the possible mechanism of which tumor-associated macrophages (TAMs) changed in PDAC. We found that the composition of TAMs subtypes, including M0, M1, and M2, was different between PDAC and ANT, which was validated in recently published single-cell RNA-seq data. Many immune cells interacted with each other to affect the TIME. There were many DEGs enriched in some pathways that could potentially change the immune cell composition. KRT6A was found to be a DEG between PDAC and ANT that overlapped with DEGs between the M0-high group and the M0-low group in TCGA datasets, and it might alter and regulate TAMs via a collection of genes including COL5A2, COL1A2, MIR3606, SPARC, and COL6A3. TAMs, which could be a target of immunotherapy, might be influenced by genes through KRT6A and indicate an undesirable prognosis in PDAC.

Spatial Density and Distribution of Tumor-Associated Macrophages Predict Survival in Non-Small Cell Lung Carcinoma.

The respective antitumoral and protumoral roles of M1 and M2 tumor-associated macrophages (TAM) typify the complexity of macrophage function in cancer. In lung cancer, density and topology of distinct TAM phenotypes at the tumor center (TC) versus the invasive margin (IM) are largely unknown. Here, we investigated TAM subtype density and distribution between TC and IM in human lung cancer and TAM associations with overall survival. Macrophages isolated from adjacent nontumor tissue (NM), the TC (TC-TAM), and the IM (IM-TAM) were analyzed with RNA-sequencing (RNA-seq). Lung tumor tissue microarrays from 104 patient samples were constructed. M1 and M2 TAMs were identified using multiplex immunofluorescence staining and a tumor cell-TAM proximity analysis was performed. RNA-seq identified marked differences among NM, TC-TAM, and IM-TAM. On the basis of a panel of five selected markers (CD68, IL12, CCR7, CD163, and ALOX15), M2 predominance over M1 and M2 proximity to tumor cells was observed, especially at IM. Tumor cell proximity to TAM was linked with tumor cell survival and hypoxia was associated with accumulation of M2 TAM. Notably, lower density of M1 TC-TAM and higher proximity of tumor cells to M2 IM-TAM or lower proximity to M1 IM-TAM were linked with poor survival. In addition, three novel molecules (UBXN4, MFSD12, and ACTR6) from RNA-seq served as potential prognostic markers for lung cancer, and M2 predominance and juxtaposition of M2 TAM near tumor cells were associated with poor survival. Together, our results reveal the marked heterogeneity of TAM populations in different tumor regions, with M2 TAM predominance, particularly at IM. SIGNIFICANCE: This study underlines the significance of the density, spatial distribution, and gene expression of TAM phenotypes as prognostic factors for overall survival in lung cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4414/F1.large.jpg.

CD68- and CD163-positive tumor-associated macrophages in triple negative cancer of the breast

Tumor-associated macrophages (TAMs) have recently been reported as an important factor in tumor growth and the progression of cancer. The prognostic significance of localizations and densities of TAMs in triple negative cancer (TNC) of the breast is not well understood. The aim of this study was to assess the localizations and densities of the TAMs subtype in TNC and examine their clinicopathological features. The study was based on 107 TNC cases operated on at Dokkyo Medical University Hospital using the pan-macrophage marker CD68 and the M2 macrophage marker CD163 in the tumor stroma (TS) and tumor nest (TN), respectively, and examined the clinicopathological significance. Multivariate Cox regression analyses revealed that age and CD163+ TAMs in both the TS and TN were independent prognostic factors for relapse-free survival and overall survival. No correlation was found between the number of CD68+ cells or the CD163/CD68 ratio either in TS or TN, or clinicopathological features. Our study found that infiltration of CD163+ TAMs, rather than CD68+, in both TS and TN was associated with poor prognosis in TNC patients by multivariate analysis. This suggests that CD163+ TAMs may affect the prognosis of TNC by not only regulating the immune reaction by TAMs in TS, but also because of their direct influence on TN.

Abstract B09: Targeting scavenger receptors for immunotherapy of cancer

Abstract Background: Tumor-associated macrophages (TAM) play an important role in tumor-promoting inflammation and have been associated with poor prognosis in many human cancers. Recently, we showed that class A scavenger receptor MARCO is a specific marker for the immune-suppressive tumor-promoting TAM subtype in different tumor models. Targeting MARCO by monoclonal antibodies (Ab) could reprogram the protumorigenic TAM towards a proinflammatory phenotype with antitumor activity, leading to decreased tumor growth and metastases formation in three different mouse tumor models. Aim(s): The current immunotherapies are estimated to treat less than 50% of all cancers; therefore, it is of high importance to develop new targets and combinatorial therapies. In this study, we aim to define the role of scavenger receptor MARCO on TAM in more detail and the mechanisms of how targeting MARCO by monoclonal Ab modulates macrophage phenotype and tumor microenvironment. Moreover, we are investigating how it can be used as a possible anticancer therapeutic approach used as single or combinatorial treatment. Results: Our recent data demonstrate that using anti-MARCO Ab in combination with other immune checkpoint inhibitors, such as anti-CTLA-4 Ab, further decreases the tumor volume by 40-50% in the B16 melanoma model. For example, different checkpoint Ab combined with anti-MARCO Ab shows a reduction from average tumor volume 500mm3 in single treatments to 250mm3 (p=0.0101) in the combinatorial treatment. Currently, we are investigating what happens in the tumor microenvironment on a cellular level after using the different combinatorial treatments. Moreover, we see increased ATP release of MARCO+ macrophages in vitro after engagement of MARCO as well as enhanced glycolysis in anti-MARCO Ab treated macrophages compared to the control group. Conclusion: Checkpoint inhibitors targeting T cells are already used in the clinics and the anti-MARCO Ab targeting TAM is a promising candidate to use in combination with checkpoint inhibitors to even further increase the survival rate of patients. The understanding of MARCO signaling and how this leads to a shift towards proinflammatory macrophages would not just benefit the field of basic macrophage biology but will also be an important step in translating the anti-MARCO Ab therapy from mice to humans as a new approach for cancer immunotherapy. Citation Format: Vanessa F. Boura, Sofia Tyystjärvi, Ganna Oliynyk, Marie Arsenian-Henriksson, Mikael C.I. Karlsson, Silke Sohn. Targeting scavenger receptors for immunotherapy of cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B09.

Tumor-associated macrophage infiltration in meningioma.

BackgroundMeningioma, a most common brain tumor, has a high rate of recurrence. Tumor-associated macrophages (TAMs) are the most abundant immune cell type in meningioma. TAMs display functional phenotypic diversity and may establish either an inflammatory and anti-tumoral or an immunosuppressive and pro-tumoral microenvironment. TAM subtypes present in meningioma and potential contribution to growth and recurrence is unknown.MethodsImmunofluorescence staining was used to quantify M1 and M2 TAM populations in tissues obtained from 30 meningioma patients. Associations between M1 and M2 cells, M1:M2 cell ratio to tumor characteristics, WHO grade, recurrence, size, location, peri-tumoral edema, and patient demographics such as age and sex were examined.ResultsTAM cells accounted for ~18% of all cells in meningioma tissues. More than 80% of infiltrating TAMs were found to be of pro-tumoral M2 phenotype and correlated to tumor size (P = .0409). M1:M2 cell ratio was significantly decreased in WHO grade II, compared to grade I tumors (P = .009). Furthermore, a 2.3-fold difference in M1:M2 ratio between primary (0.14) and recurrent (0.06) tumors was observed (n = 18 and 12 respectively, P = .044).ConclusionThis study is the first to confirm existence of pro-tumoral M2 TAMs in the meningioma microenvironment, emphasizing its potential role in tumor growth and recurrence.

Alteration of Tumor-Associated Macrophage Subtypes Mediated by KRT6A in Pancreatic Ductal Adenocarcinoma

Alteration of Tumor-Associated Macrophage Subtypes Mediated by KRT6A in Pancreatic Ductal Adenocarcinoma

The Clinical Significance of Tumor Associated Macrophages in Myelodysplastic Syndromes

Objective:The purpose of this study is to investigate the relationship between the infiltration of tumor associated macrophages (TAMs) and the disease risk stratification and survival of patients with myelodysplastic syndrome (MDS) and to explore the role of TAMs in the clinical prognosis.Methods:We retrospectively collected and analyzed 115 patients initially diagnosed wih myelodysplastic syndromes from January, 2010 to July, 2017 in West China Hospital of Sichuan University. Both bone marrow biopsy specimens and clinical data of the patients enrolled were collected. All patients were assessed prognosis by international prognostic scoring system (IPSS). We quantified the involvement of macrophage (MΦ), alternatively activated macrophage (M2 MΦ) and classic activated macrophage (M1 MΦ) in bone marrow specimen by staining with anti-CD68 monoclonal antibody, anti-CD163 monoclonal antibody, and anti-iNOS monoclonal antibody respectively. Log-rank test was used to evaluate the difference of overall survival (OS) among different subgroups. Logistic regression was used to evaluate the effect of clinical parameters on patients' OS. Cox proportional-hazards models were used to estimate the independent risk factors influencing the prognosis of patients.Results:1 In the high risk group of MDS, the composition of CD163+MΦ was higher than that of the low risk group(p < 0.001). In the low risk group of MDS, the composition of iNOS+ MΦ was higher than that of the group with high risk(p < 0.001).2 The median survival time and 3-year survival rate in the high CD163+MΦinfiltration group were significantly lower than those in the low infiltration group (13 months vs 43 months, 27% vs 64%, Log-rank test, P<0.001). The median survival time and 3-year survival rate in high iNOS+MΦ infiltration group were significantly higher than those in low infiltration group (42. 5 months vs 11 months, 65% vs 27% Log-rank test, P< 0.001).3 According to the infiltration degree of iNOS+MΦ and CD163+MΦ, the M1 (iNOShigh/CD 163low)and M2 TA(iNOSlow/CD163high) MΦ were further distinguished (The median OS were 53m and 15m respectively, p< 0.001).4 In multivariate analysis, high infiltration of CD163+MΦ and CD68+MΦ, low infiltration of iNOS+MΦ and low PLT level were independent risk factors for patients' OS .Conclusion and Discuss:The degree of bone marrow TAMs subtype infiltration in MDS patients was associated with disease risk group. CD163+M Φ was the main TAMs in the high risk group of MDS,while iNOS+M Φ was the main TAMs in the low risk group. There was a positive correlation between the infiltration of M1-TAMs and OS. On the contrary, there was a negative correlation between the infiltration of M2-TAMs and OS. Analyzing TAMs subsets in bone marrow of patients with MDS is helpful to evaluate disease risk and prognosis. DisclosuresNo relevant conflicts of interest to declare.

Preclinical and Clinical Therapeutic Strategies Affecting Tumor-Associated Macrophages in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) most often develops in patients with underlying liver disease characterized by chronic nonresolving inflammation. Tumor-associated macrophages (TAMs) are one of the most abundant immune cell populations within the tumoral microenvironment. As key actors of cancer-related inflammation, they promote tumor growth by suppression of effective anticancer immunity, stimulation of angiogenesis, and tissue remodeling. Therefore, they have become an attractive and promising target for immunotherapy. The heterogeneity of TAM subtypes and their origin and dynamic phenotype during the initiation and progression of HCC has been partially unraveled and forms the base for the development of therapeutic agents. Current approaches are aimed at decreasing the population of TAMs by depleting macrophages present in the tumor, blocking the recruitment of bone marrow-derived monocytes, and/or functionally reprogramming TAMs to antitumoral behavior. In this review, the preclinical evolution and hitherto clinical trials for TAM-targeted therapy in HCC will be highlighted.

CD163+ Tumor Associated Macrophages Predict Inferior Outcome in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP

Tumor-associated macrophages (TAMs), as the major component in tumor microenvironment, have been reported to correlate with the prognosis in diffuse large B-cell lymphoma (DLBCL). However due to the different subtypes of TAMs and the given therapy regimen, the prognostic value of TAMs in DLBCL patients remains controversial. To explore the prognostic significance of different TAMs subtypes in DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), we retrospectively analyzed 77 de novo DLBCL patients in present study.TAM markers including CD68 and CD163 were evaluated by immunohistochemistry. The cutoff value of CD68, CD163 and CD163/CD68 ratio was determined by receiver operating characteristic curve. In a total of 77 patients, CD68 high expression was found in71.4 %( 55/77) DLBCL patients and CD163 high expression in 51.4 %( 40/77 patients. Patients with high CD163 expression were more present with extranodal sites (P =0.049). However other clinical parameters including age, gender, Ann Arbor stage, performance stage, B symptoms, LDH and international prognostic index (IPI) showed no difference in patients with high and low CD68 or CD163 expression (P >0.05). CD68 expression has less effect on overall survival (OS) and event-free survival (EFS) (P =0.852, 0.782). However, high CD163 expression showed poor OS and EFS in DLBCL patients (P =0.006, 0.004) and also high CD163/CD68 ratio (P <0.001, 0.001). The multivariate analysis revealed that the high CD163 expression and CD163/CD68 ratio remained unfavorable factors for both OS (P =0.094, 0.002) and EFS (P =0.044, 0.016) independent of IPI. In conclusion, our date suggest that high CD163+ TAMs in tumor microenvironment may imply poor outcome in DLBCL patients treated with R-CHOP, but not CD68+ TAMs. DisclosuresNo relevant conflicts of interest to declare.