scholarly journals Tumor-Associated Macrophages in Tumor Immunity

2020 ◽  
Vol 11 ◽  
Author(s):  
Yueyun Pan ◽  
Yinda Yu ◽  
Xiaojian Wang ◽  
Ting Zhang
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Immune Cell ◽  
Malignant Tumors ◽  
Treatment Strategies ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
M2 Macrophages ◽  
Tumor Associated Macrophages ◽  
Mediate Cytotoxicity

Tumor-associated macrophages (TAMs) represent one of the main tumor-infiltrating immune cell types and are generally categorized into either of two functionally contrasting subtypes, namely classical activated M1 macrophages and alternatively activated M2 macrophages. The former typically exerts anti-tumor functions, including directly mediate cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) to kill tumor cells; the latter can promote the occurrence and metastasis of tumor cells, inhibit T cell-mediated anti-tumor immune response, promote tumor angiogenesis, and lead to tumor progression. Both M1 and M2 macrophages have high degree of plasticity and thus can be converted into each other upon tumor microenvironment changes or therapeutic interventions. As the relationship between TAMs and malignant tumors becoming clearer, TAMs have become a promising target for developing new cancer treatment. In this review, we summarize the origin and types of TAMs, TAMs interaction with tumors and tumor microenvironment, and up-to-date treatment strategies targeting TAMs.

Mesenchymal Stem Cells and Cancer Stem Cells: An Overview of Tumor-Mesenchymal Stem Cell Interaction for therapeutic interventions

2021 ◽  
Vol 22 ◽  
Author(s):  
Soheila Montazersaheb ◽  
Ezzatollah Fathi ◽  
Ayoub Mamandi ◽  
Raheleh Farahzadi ◽  
Hamid Reza Heidari
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Cell Interaction ◽  
Therapeutic Interventions ◽  
Tumorigenic Potential ◽  
Different Types

: Tumors are made up of different types of cancer cells that contribute to tumor heterogeneity. Among these cells, cancer stem cells (CSCs) have a significant role in the onset of cancer and development. Like other stem cells, CSCs are characterized by the capacity for differentiation and self-renewal. A specific population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into mesoderm-specific cells. The pro-or anti-tumorigenic potential of MSCs on the proliferation and development of tumor cells has been reported as contradictory results. Also, tumor progression is specified by the corresponding tumor cells like the tumor microenvironment. The tumor microenvironment consists of a network of reciprocal cell types such as endothelial cells, immune cells, MSCs, and fibroblasts as well as growth factors, chemokines, and cytokines. In this review, recent findings related to the tumor microenvironment and associated cell populations, homing of MSCs to tumor sites, and interaction of MSCs with tumor cells will be discussed.

scholarly journals CD16A-Specific Tetravalent Bispecific Immune Cell Engagers Potently Induce Antibody-Dependent Cellular Phagocytosis (ADCP) on Macrophages

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1111-1111
Author(s):  
Susanne Wingert ◽  
Uwe Reusch ◽  
Armin Beez ◽  
Jens Pahl ◽  
Adelheid Cerwenka ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Tumor Cells ◽  
Research Funding ◽  
Immune Cell ◽  
Major Constituent ◽  
Target Cells ◽  
M2 Macrophages ◽  
Macrophage Subtypes

Abstract Introduction Affimed has developed high affinity tetravalent bispecific immune cell engagers for redirected optimized cell killing (ROCK platform). Using anti-CD16A and anti-tumor target-specific antibody domains, the engagers activate NK cells to efficiently kill target cells. The most advanced ROCK-based immune cell engager, AFM13, targeting CD30 on tumor cells and CD16A on immune effectors, is currently being evaluated in several clinical trials to treat CD30-positive malignancies. Based on the fact that CD16A is not exclusively expressed on NK cells, but also on macrophages, we hypothesized that CD16A-specific immune cell engagers would also be able to activate CD16A expressing macrophages through antibody-dependent cellular phagocytosis (ADCP) contributing to anti-tumor response. Macrophages are an essential component of the innate immune system and are a major constituent of normal tissues. They can be broadly classified into different subtypes including M1 (classically activated, generally characterized as pro-inflammatory and immuno-supportive) and M2 (alternatively activated, primarily of an anti-inflammatory profile) subtypes. Those subtypes greatly differ in their phenotype and function and appear to be highly plastic. While M1 macrophages are generally considered to be tumoricidal, M2 macrophages are mostly tumorigenic, depending on their context within the tumor microenvironment. Therapeutic agents focusing on macrophages such as the CD47/SIRPa axis, CSF-1R antibodies and elimination of tumor-associated macrophages (TAMs) have recently come into focus in immuno-oncology. Methods Peripheral monocytes derived from primary human hematopoietic cells of healthy donors were used to generate various macrophage subtypes (unpolarized macrophages, M1, M2a, M2c) in vitro using well-defined cytokine cocktails. These subtypes were characterized phenotypically for their CD16A expression and a wide number of additional markers. Subsequently, they were used to investigate the ability of a number of different CD16A-specific immune cell engagers derived from Affimed´s ROCK platform and control antibodies in vitro to activate and induce ADCP of target cells by flow cytometry and microscopy. Results We demonstrated that all of the macrophage subtypes generated in this study expressed CD16A and mediated ADCP of tumor cells. In addition, we showed that ADCP of tumor cells by several CD16A-specific engagers was both fast and robust for all investigated macrophage subtypes. Specifically, ADCP was detected as early as 2 hours after co-incubation of tumor cells with M1 or M2 macrophages and CD16A-specific immune cell engagers. Using appropriate control antibodies, it was demonstrated that ADCP mediated by CD16A-specific immune cell engagers was selective and at least as potent as ADCP mediated by classical monoclonal antibodies pan-specific for Fc-gamma receptors. Summary and conclusion: We have demonstrated a new mechanism whereby Affimed´s CD16A-specific immune cell engaging antibodies eliminate tumor cells by ADCP, mediated by different subsets of macrophages. Our data suggest that these antibodies may have the potential to boost tumoricidal function within the tumor microenvironment. Future directions of leveraging innate immunity as a therapeutic option in immuno-oncology will be presented. Disclosures Wingert: Affimed: Employment. Reusch:Affimed: Employment. Beez:Affimed: Employment. Pahl:Affimed: Research Funding. Cerwenka:Affimed: Research Funding; Dragonfly Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Koch:Affimed GmbH: Employment. Treder:Affimed GmbH: Employment.

RRx-001 is a phase III aerospace-derived small molecule that immunonormalizes the tumor microenvironment.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 156-156
Author(s):  
Pedro Cabrales
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Immune Cell ◽  
Cell Activity ◽  
Phase Iii ◽  
Cell Infiltration ◽  
Immune Checkpoints ◽  
Vascular Normalization ◽  
Tumor Associated Macrophages ◽  
Macrophage Phagocytosis

156 Background: Tumor associated macrophages (TAMs) with M2-like phenotypes produce angiogenic factors and cytokines which lead to vascular immaturity. M2 cytokines also impair immune cell activity. CD47 and SIRP⍺ are innate immune checkpoints which inhibit macrophage phagocytosis and enhance M2 polarization. Disruption of the CD47/SIRP⍺ axis polarize TAMs away from an M2-like phenotype to normalize tumor vessels and stimulate antitumor immunity. Normalized vessels facilitate delivery of drugs and immune cells and also sensitizes tumors to therapy and promotes M1-like TAM phenotype. RRx-001 modulates TAM infiltration and phenotype via CD47/SIRP⍺ downregulation, which normalizes both the tumor vasculature, and the immune cell milieu. Methods: The effect of RRx-001 on intratumoral blood flow was evaluated both preclinically and clinically with dynamic contrast MRI. An in vitro phagocytotic assay was used to determine whether RRx-001 promoted engulfment of A549 tumor cells by macrophages. Transcriptional mRNA profiling in murine tumor associated macrophages (TAMs) was performed to analyze the cytokine profile of TAMs in the presence or absence of RRx-001. Athymic mice with intracranial GBM43 were administered RRx-001 (10 mg/kg) followed 4 hours later by 0.4 mg of irinotecan by tail vein on days 12, 18, 24 and 30 after implantation of tumor cells. Mice were euthanized 24 hours after last irinotecan administration, with brains immediately resected and tumor tissue dissected prior to snap-freezing by immersion in liquid nitrogen. Results: RRx-001 was shown to induce: vascular normalization with increased intratumoral perfusion, dual downregulation of CD47 and SIRP⍺, increased phagocytosis, improved delivery of chemotherapy and increased T cell infiltration. Conclusions: RRx-001 leads to vascular normalization and enhanced delivery of chemotherapy and immune cell infiltration. The increase in tumor perfusion diminishes hypoxia and also serves to polarize TAMs away from an M2-like state. These results also suggest and are borne out by clinical biopsies that the effect of RRx-001 depends on the number of TAMs present in the tumor microenvironment with higher numbers leading to better activity.

The Critical Interaction Between Epstein-Barr Virus (EBV) Positive B-Cells and Tumor Associated Macrophages (TAMs)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2989-2989 ◽  
Author(s):  
Ai Sato ◽  
Natsuko Yamakawa ◽  
Kazuki Okuyama ◽  
Ai Kotani ◽  
Naoya Nakamura ◽  
...  
Keyword(s):  
B Cells ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
B Cell Lymphoma ◽  
The Elderly ◽  
M2 Macrophages ◽  
Tumor Associated Macrophages ◽  
Lymphoma Cells ◽  
The Impact

Abstract Introduction: EBV positive diffuse large B-cell lymphoma of the elderly (EBV positive DLBCL, elderly) has been newly categorized in 2008 WHO classification. The incidence is higher in Asian countries than Western countries. The prognosis of DLBCL has been improved by the introduction of rituximab, while EBV positive DLBCL remains unknown. Recently we reported that EBV positive DLBCL of the elderly did have quit inferior prognosis than EBV negative DLBCL. The mechanism lying under the inferiority has yet been elucidated. We hypothesize that tumor microenvironment plays a role in the mechanism, as EBV related lymphoma are usually accompanied with massive infiltration of non-tumor cells. We have previously found that tumor secreted small RNAs were selectively taken by macrophages and dramatically change the character into tumor supporting phenotype in the EBV positive lymphoma. Accordingly, we focus the interaction between tumor cells and macrophages in EBV positive lymphoma microenvironment. Methods: We investigated the number of CD163-positive macrophage (CD163+M2) in the DLBCL specimen with and without EBV positivity. The effect of EBV positivity in the tumor cells on the macrophages infiltrated in the tumor were studied by use of the coculture system using human monocytic cell line (THP-1) and human Burkitt lymphoma cells lines (Akata) which has two subclones such as EBV positive and negative. PMA-induced macrophages from THP1 cells were cocultured with EBV positive or negative Akata, then the expression of the several cytokines such as TNF-a, IL-10, CXCL10, and VEGF were measured by real-time PCR. Finally, we tried to clarify the impact of the macrophages on tumor formation in vivo by using xeno-transplantation model. Hematopoietic humanized NOG mice were infected with EBV to induce EBV related lymphoproliferative disease (LPD). After the appearance of symptoms of the LPD such as body weight loss, mice were treated with Clodronate to deplete macrophages. Result: The multivariate analysis for DLBCL patients demonstrated the statistically significant association between both high scores of CD163+M2 macrophages (CD163-positive cell > 20%) and EBV positivity, and poor prognosis (p = 0.0084, 0.0020, respectively.), which implies that EBV affected the quantity of CD163+M2 macrophages in the tumor microenvironment. Co-culture of THP1 with EBV positive lymphoma cells significantly upregulated CXCL10 and VEGF, when compared with EBV negative cells. (p = 0.0073, 0.0161, respectively.). (Figure 1) Most surprisingly, EBER positive B cells almost completely disappeared by macrophage depletion by Clodronate treatment (Figure 2). These results suggest that the macrophages in the EBV positive tumor microenvironment are crucial for survival of EBV+ tumor cells. Conclusion: EBV status of the lymphoma cells affected on TAMs in the way such as up-regulation of CXCR10 and VGEF, angiogenetic factors which are presumed to support tumor survival. The in vivo depletion of macrophages by Clodronate also demonstrated that they were indispensable for EBV positive tumor cell survival. Taken together, the interaction of EBV positive tumor cells and tumor associated macrophages is of crucial importance in the biology and formation of EBV positive lymphoma. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Katrin Schlie ◽  
Jaeline E. Spowart ◽  
Luke R. K. Hughson ◽  
Katelin N. Townsend ◽  
Julian J. Lum
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Patient Treatment ◽  
Low Oxygen ◽  
Tumor Environment ◽  
And Function ◽  
The Impact

Hypoxia is a signature feature of growing tumors. This cellular state creates an inhospitable condition that impedes the growth and function of all cells within the immediate and surrounding tumor microenvironment. To adapt to hypoxia, cells activate autophagy and undergo a metabolic shift increasing the cellular dependency on anaerobic metabolism. Autophagy upregulation in cancer cells liberates nutrients, decreases the buildup of reactive oxygen species, and aids in the clearance of misfolded proteins. Together, these features impart a survival advantage for cancer cells in the tumor microenvironment. This observation has led to intense research efforts focused on developing autophagy-modulating drugs for cancer patient treatment. However, other cells that infiltrate the tumor environment such as immune cells also encounter hypoxia likely resulting in hypoxia-induced autophagy. In light of the fact that autophagy is crucial for immune cell proliferation as well as their effector functions such as antigen presentation and T cell-mediated killing of tumor cells, anticancer treatment strategies based on autophagy modulation will need to consider the impact of autophagy on the immune system.

scholarly journals Inflammation and Cancer: Extra- and Intracellular Determinants of Tumor-Associated Macrophages as Tumor Promoters

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Gabor J. Szebeni ◽  
Csaba Vizler ◽  
Klara Kitajka ◽  
Laszlo G. Puskas
Keyword(s):  
Tumor Microenvironment ◽  
Macrophage Polarization ◽  
Myeloid Cells ◽  
Therapeutic Interventions ◽  
Tumor Associated Macrophages ◽  
Poor Survival ◽  
Cell Functions ◽  
Intracellular Signals ◽  
Ontogenetic Diversity ◽  
Cell Dissemination

One of the hallmarks of cancer-related inflammation is the recruitment of monocyte-macrophage lineage cells to the tumor microenvironment. These tumor infiltrating myeloid cells are educated by the tumor milieu, rich in cancer cells and stroma components, to exert functions such as promotion of tumor growth, immunosuppression, angiogenesis, and cancer cell dissemination. Our review highlights the ontogenetic diversity of tumor-associated macrophages (TAMs) and describes their main phenotypic markers. We cover fundamental molecular players in the tumor microenvironment including extra- (CCL2, CSF-1, CXCL12, IL-4, IL-13, semaphorins, WNT5A, and WNT7B) and intracellular signals. We discuss how these factors converge on intracellular determinants (STAT3, STAT6, STAT1, NF-κB, RORC1, and HIF-1α) of cell functions and drive the recruitment and polarization of TAMs. Since microRNAs (miRNAs) modulate macrophage polarization key miRNAs (miR-146a, miR-155, miR-125a, miR-511, and miR-223) are also discussed in the context of the inflammatory myeloid tumor compartment. Accumulating evidence suggests that high TAM infiltration correlates with disease progression and overall poor survival of cancer patients. Identification of molecular targets to develop new therapeutic interventions targeting these harmful tumor infiltrating myeloid cells is emerging nowadays.

scholarly journals Assessment of phagocytic activity in live macrophages-tumor cells co-cultures by Confocal and Nomarski Microscopy

2017 ◽  
Vol 2 (1) ◽  
Author(s):  
Dalia Martinez-Marin ◽  
Courtney Jarvis ◽  
Thomas Nelius ◽  
Stéphanie Filleur
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Phagocytic Activity ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Functional Assay ◽  
Loss Of Function ◽  
Multiple Cancer

Abstract Macrophages have been recognized as the main inflammatory component of the tumor microenvironment. Although often considered as beneficial for tumor growth and disease progression, tumor-associated macrophages have also been shown to be detrimental to the tumor depending on the tumor microenvironment. Therefore, understanding the molecular interactions between macrophages and tumor cells in relation to macrophages functional activities such as phagocytosis is critical for a better comprehension of their tumor-modulating action. Still, the characterization of these molecular mechanisms in vivo remains complicated due to the extraordinary complexity of the tumor microenvironment and the broad range of tumor-associated macrophage functions. Thus, there is an increasing demand for in vitro methodologies to study the role of cell–cell interactions in the tumor microenvironment. In the present study, we have developed live co-cultures of macrophages and human prostate tumor cells to assess the phagocytic activity of macrophages using a combination of Confocal and Nomarski Microscopy. Using this model, we have emphasized that this is a sensitive, measurable, and highly reproducible functional assay. We have also highlighted that this assay can be applied to multiple cancer cell types and used as a selection tool for a variety of different types of phagocytosis agonists. Finally, combining with other studies such as gain/loss of function or signaling studies remains possible. A better understanding of the interactions between tumor cells and macrophages may lead to the identification of new therapeutic targets against cancer.

scholarly journals MIXTURE: an improved algorithm for immune tumor microenvironment estimation based on gene expression data

2019 ◽  
Author(s):  
Elmer A. Fernández ◽  
Yamil D. Mahmoud ◽  
Florencia Veigas ◽  
Darío Rocha ◽  
Mónica Balzarini ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cell ◽  
Therapy Response ◽  
Cell Types ◽  
Gene Signature ◽  
Response To Therapy ◽  
Support Vector ◽  
Data Sets ◽  
Cell Type ◽  
Before And After

AbstractRNA sequencing has proved to be an efficient high-throughput technique to robustly characterize the presence and quantity of RNA in tumor biopsies at a given time. Importantly, it can be used to computationally estimate the composition of the tumor immune infiltrate and to infer the immunological phenotypes of those cells. Given the significant impact of anti-cancer immunotherapies and the role of the associated immune tumor microenvironment (ITME) on its prognosis and therapy response, the estimation of the immune cell-type content in the tumor is crucial for designing effective strategies to understand and treat cancer. Current digital estimation of the ITME cell mixture content can be performed using different analytical tools. However, current methods tend to over-estimate the number of cell-types present in the sample, thus under-estimating true proportions, biasing the results. We developed MIXTURE, a noise-constrained recursive feature selection for support vector regression that overcomes such limitations. MIXTURE deconvolutes cell-type proportions of bulk tumor samples for both RNA microarray or RNA-Seq platforms from a leukocyte validated gene signature. We evaluated MIXTURE over simulated and benchmark data sets. It overcomes competitive methods in terms of accuracy on the true number of present cell-types and proportions estimates with increased robustness to estimation bias. It also shows superior robustness to collinearity problems. Finally, we investigated the human immune microenvironment of breast cancer, head and neck squamous cell carcinoma, and melanoma biopsies before and after anti-PD-1 immunotherapy treatment revealing associations to response to therapy which have not seen by previous methods.

Patient-derived micro-organospheres recapitulate tumor microenvironment and heterogeneity for precision oncology.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3076-3076
Author(s):  
Shengli Ding ◽  
Zhaohui Wang ◽  
Marcos Negrete Obando ◽  
Grecia rivera Palomino ◽  
Tomer Rotstein ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Stromal Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Tumor Biology ◽  
Cell Types ◽  
Precision Oncology ◽  
Original Tumor

3076 Background: Preclinical models that can recapitulate patients’ intra-tumoral heterogeneity and microenvironment are crucial for tumor biology research and drug discovery. In particular, the ability to retain immune and other stromal cells in the microenvironment is vital for the development of immuno-oncology assays. However, current patient-derived organoid (PDO) models are largely devoid of immune components. Methods: We first developed an automated microfluidic and membrane platform that can generate tens of thousands of micro-organospheres from resected or biopsied clinical tumor specimens within an hour. We next characterized growth rate and drug response of micro-organospheres. Finally, extensive single-cell RNA-seq profiling were performed on both micro-organospheres and original tumor samples from lung, ovarian, kidney, and breast cancer patients. Results: Micro-organospheres derived from clinical tumor samples preserved all original tumor and stromal cells, including fibroblasts and all immune cell types. Single-cell analysis revealed that unsupervised clustering of tumor and non-tumor cells were identical between original tumors and the derived micro-organospheres. Quantification showed similar cell composition and percentages for all cell types and also preserved functional intra-tumoral heterogeneity.. An automated, end-to-end, high-throughput drug screening pipeline demonstrated that matched peripheral blood mononuclear cells (PBMCs) from the same patient added to micro-organospheres can be used to assess the efficacy of immunotherapy moieties. Conclusions: Micro-organospheres are a rapid and scalable platform to preserve patient tumor microenvironment and heterogeneity. This platform will be useful for precision oncology, drug discovery, and immunotherapy development. Funding sources: NIH U01 CA217514, U01 CA214300, Duke Woo Center for Big Data and Precision Health

scholarly journals Melanoma-specific bcl-2 promotes a protumoral M2-like phenotype by tumor-associated macrophages

2020 ◽  
Vol 8 (1) ◽  
pp. e000489 ◽  
Author(s):  
Marta Di Martile ◽  
Valentina Farini ◽  
Francesca Maria Consonni ◽  
Daniela Trisciuoglio ◽  
Marianna Desideri ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Macrophage Polarization ◽  
Melanoma Cells ◽  
Response To Therapy ◽  
Major Constituent ◽  
M2 Macrophage ◽  
Tumor Associated Macrophages

BackgroundA bidirectional crosstalk between tumor cells and the surrounding microenvironment contributes to tumor progression and response to therapy. Our previous studies have demonstrated that bcl-2 affects melanoma progression and regulates the tumor microenvironment. The aim of this study was to evaluate whether bcl-2 expression in melanoma cells could influence tumor-promoting functions of tumor-associated macrophages, a major constituent of the tumor microenvironment that affects anticancer immunity favoring tumor progression.MethodsTHP-1 monocytic cells, monocyte-derived macrophages and melanoma cells expressing different levels of bcl-2 protein were used. ELISA, qRT-PCR and Western blot analyses were used to evaluate macrophage polarization markers and protein expression levels. Chromatin immunoprecipitation assay was performed to evaluate transcription factor recruitment at specific promoters. Boyden chamber was used for migration experiments. Cytofluorimetric and immunohistochemical analyses were carried out to evaluate infiltrating macrophages and T cells in melanoma specimens from patients or mice.ResultsHigher production of tumor-promoting and chemotactic factors, and M2-polarized activation was observed when macrophages were exposed to culture media from melanoma cells overexpressing bcl-2, while bcl-2 silencing in melanoma cells inhibited the M2 macrophage polarization. In agreement, the number of melanoma-infiltrating macrophages in vivo was increased, in parallel with a greater expression of bcl-2 in tumor cells. Tumor-derived interleukin-1β has been identified as the effector cytokine of bcl-2-dependent macrophage reprogramming, according to reduced tumor growth, decreased number of M2-polarized tumor-associated macrophages and increased number of infiltrating CD4+IFNγ+and CD8+IFNγ+effector T lymphocytes, which we observed in response to in vivo treatment with the IL-1 receptor antagonist kineret. Finally, in tumor specimens from patients with melanoma, high bcl-2 expression correlated with increased infiltration of M2-polarized CD163+macrophages, hence supporting the clinical relevance of the crosstalk between tumor cells and microenvironment.ConclusionsTaken together, our results show that melanoma-specific bcl-2 controls an IL-1β-driven axis of macrophage diversion that establishes tumor microenvironmental conditions favoring melanoma development. Interfering with this pathway might provide novel therapeutic strategies.

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