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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 enzyme glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyzes the formation of pyroglutamate residues at the NH2-terminus of proteins, thereby influencing their biological properties. A number of studies have implicated QPCTL in the regulation of chemokine stability. Furthermore, QPCTL activity has recently been shown to be critical for the formation of the high-affinity SIRPa binding site of the CD47 "don't-eat-me" protein. Based on the latter data, interference with QPCTL activity--and hence CD47 maturation--may be proposed as a means to promote anti-tumor immunity. However, the pleiotropic activity of QPCTL makes it difficult to predict the effects of QPCTL inhibition on the tumor microenvironment (TME). Using a syngeneic mouse melanoma model, we demonstrate that QPCTL deficiency alters the intra-tumoral monocyte-to-macrophage ratio, results in a profound increase in the presence of proinflammatory cancer-associated fibroblasts (CAFs) relative to immunosuppressive TGF-ß1-driven CAFs, and leads to an increased IFN and decreased TGF-ß transcriptional response signature in tumor cells. Importantly, the functional relevance of the observed TME remodeling is demonstrated by the synergy between QPCTL deletion and anti PD-L1 therapy, sensitizing an otherwise refractory melanoma model to anti-checkpoint therapy. Collectively, these data provide support for the development of strategies to interfere with QPCTL activity as a means to promote tumor-specific immunity. [ABSTRACT FROM AUTHOR]

The application of monoclonal antibodies (mAbs) for the treatment of melanoma has significantly improved the clinical management of this malignancy over the last decade. Currently approved mAbs for melanoma enhance T cell effector immune responses by blocking immune checkpoint molecules PDL1/PD-1 and CTLA-4. However, more than half of patients do not benefit from treatment. Targeting the prominent myeloid compartment within the tumor microenvironment, and in particular the everabundant tumor-associated macrophages (TAMs), may be a promising strategy to complement existing therapies and enhance treatment success. TAMs are a highly diverse and plastic subset of cells whose protumor properties can support melanoma growth, angiogenesis and invasion. Understanding of their diversity, plasticity and multifaceted roles in cancer forms the basis for new promising TAM-centered treatment strategies. There are multiple mechanisms by which macrophages can be targeted with antibodies in a therapeutic setting, including by depletion, inhibition of specific pro-tumor properties, differential polarization to pro-inflammatory states and enhancement of antitumor immune functions. Here, we discuss TAMs in melanoma, their interactions with checkpoint inhibitor antibodies and emerging mAbs targeting different aspects of TAM biology and their potential to be translated to the clinic. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAM) and cancer-associated fibroblasts (CAF) and their precursor mesenchymal stromal cells (MSC) are often detected together in tumors, but how they cooperate is not well understood. Here, we show that TAM and CAF are the most abundant nonmalignant cells and are present together in untreated human neuroblastoma (NB) tumors that are also poorly infiltrated with T and natural killer (NK) cells. We then show that MSC and CAF-MSC harvested from NB tumors protected human monocytes (MN) from spontaneous apoptosis in an interleukin (IL)-6 dependent mechanism. The interactions of MN and MSC with NB cells resulted in a significant induction or increase in the expression of several pro-tumorigenic cytokines/chemokines (TGF-β1, MCP-1, IL-6, IL-8, and IL-4) but not of antitumorigenic cytokines (TNF-α, IL-12) by MN or MSC, while also inducing cytokine expression in quiescent NB cells. We then identified a TGF-β1/IL-6 pathway where TGF-β1 stimulated the expression of IL-6 in NB cells and MSC, promoting TAM survival. Evidence for the contribution of TAM and MSC to the activation of this pathway was then provided in xenotransplanted NB tumors and patients with primary tumors by demonstrating a direct correlation between the presence of CAF and p-SMAD2 and p-STAT3. The data highlight a new mechanism of interaction between TAM and CAF supporting their pro-tumorigenic function in cancer. [ABSTRACT FROM AUTHOR]

M2-like tumor-associated macrophages promote tumor progression by establishing an immunosuppressive tumor microenvironment. The phenotype and activity of immunosuppressive macrophages are related to their mitochondrial metabolism. Thus, we studied if drugs targeting mitochondrial metabolic pathways can repolarize macrophages from M2 into an M1-like phenotype or can prevent M0-to-M2 polarization. The drugs selected are clinically approved or in clinical trials and target M2-specific metabolic pathways: fatty acid oxidation (Perhexiline and Trimetazidine), glutaminolysis (CB-839), PPAR activation (HX531), and mitochondrial electron transport chain (VLX-600). Murine bone marrow-derived macro-phages were either polarized to M2 using IL-4 in the presence of the drugs or polarized first into M2 and then treated with the drugs in presence of IFN-γ for re-polarization. Targeting both fatty acid oxidation with Perhexiline or the electron transport chain with VLX-600 in the presence of IFN-γ, impaired mitochondrial basal, and maximal respiration and resulted in M2 to M1-like re-polarization (increased iNOS expression, NO production, IL-23, IL-27, and TNF-α secretion), similar to LPS+IFN-γ re-polarization. Moreover, drug-induced macrophage re-polarization resulted in a strong tumor-cytotoxic activity. Furthermore, the polarization of M0- to M2-like macrophages was impaired by CB-839, Trimetazidine, HX531, and Perhexiline, while Hx531 and Perhexiline also reduced MCP-1 secretion. Our results show that by targeting cell metabolism, macrophages could be re-polarized from M2- into an anti-tumoral M1-like phenotype and that M0-to-M2 polarization could be prevented. Overall, this study provides rational for the use of clinically applicable drugs to change an immunosuppressive tumor environment into a pro-inflammatory tumor environment that could support cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Exosomes are extracellular vesicles released from numerous types of cells that are involved in multiple tumors development. Exosomes contribute to the modulation of tumor microenvironment (TME) through intercellular communication. As essential immune stromal cells in the TME, tumor-associated macrophages (TAMs) participate in tumor development by mediating angiogenesis, metastasis, chemoresistance, and immune escape. Due to communication with multiple cells in the TME, they exhibit plasticity and heterogeneity during the progress of polarization from monocytes to macrophages. Previous studies suggest that targeting TAMs is a promising therapeutic strategy; however, the detailed mechanism by which TAMs regulate tumor development still remains unclear. In this review, we provide an overview of the roles of exosomes as messengers in the communication between tumor cells and polarization of TAMs; we also describe the effects of their interaction on tumor development. Finally, we comprehensively discussed the potential application of exosomes as the promising tumor immunotherapy strategy. [ABSTRACT FROM AUTHOR]

An inflammatory microenvironment has been shown to play an important role in the growth and metastasis of tumors. The NLRP3 inflammasome is a multi-protein complex of the innate immune system that is responsible for the production of the potent inflammatory cytokine IL-1β. Tumor- associated macrophages (TAM) are an expanded population of immune cells found in the tumor microenvironment that can promote the initiation and metastasis of tumor cells. Their presence has been correlated with disease burden, highlighting the therapeutic potential of targeting this population. However, to date clinically relevant pharmacologic strategies to target TAM remain elusive. Here, we show that in vitro generated TAM harbor NLRP3 inflammasome components and produce IL-1β. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK), is in clinical use for the treatment of B- cell malignancies. We report that BTK is expressed by human in vitro generated TAM and murine macrophages and that it physically associates with the NLRP3 inflammasome. Furthermore, ibrutinib is able to inhibit BTK phosphorylation in TAM generated in vitro. Treatment of TAM with ibrutinib significantly impaired the ability of these cells to produce IL-1β. The present study provides evidence that BTK physically associates with the NLRP3 inflammasome and that inhibition of BTK with ibrutinib can impair the production of IL-1β by in vitro generated TAM. Thus, ibrutinib could potentially be of clinical use in abrogating inflammation-associated cancer progression and the immune-suppressive effects of myeloid cells within the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Objectives: The interaction between the quorum sensing (QS) molecules of gut microbiota and the immunity of colorectal cancer (CRC) has not been investigated before. Methods: We measured the concentration of autoinducer-2 (AI-2) in samples of stool, colorectal tissue, saliva and serum of CRC patients, and compared this to AI-2 levels in colorectal adenoma (AD) and normal colon mucosa (NC). To explore the activated signaling pathways involved, we utilized AI-2 extracted from Fusobacterium nucleatum to stimulate macrophages and validated these in vitro findings in human CRC tissues. Results: The AI-2 concentration in both colorectal tissue and stool of CRC patients was significantly higher when compared to that in AD and NC (all P values <.01). The AI-2 concentration along with the progression of CRC in both tissues and stools was significantly increased (P=.045，P=.0003, respectively). After AI-2 stimulation, TNFSF9 was the most significantly increased protein in macrophage cells (P <.01). TNFSF9 expression was significantly higher in CRC tissues when compared to NCs (P<.0001), which was mainly derived from macrophages in the tumor microenvironment. Moreover, AI-2 level was positively associated with CD3 + T cell numbers (P=.0462), and negatively associated with CD4/CD8 ratio (P=.0113) within CRC tissues. Conclusions: We demonstrated for the first time that AI-2 may serve as a novel marker for screening CRC in the clinic. AI-2 was associated with tumor immunity in CRCs through tumor-associated macrophages and CD4/CD8 ratio in a TNFSF9-dependent manner. [ABSTRACT FROM AUTHOR]

Infiltrating myeloid derived suppressor cells and tumor-associated macrophages (TAMs) are important components of the immunosuppressive tumor microenvironment. We recently reported that tasquinimod, which binds to S100A9, impairs both infiltration and function of these cells. Here we discuss the underlying mechanisms responsible for targeting multiple suppressive populations and the modulation of the tumor microenvironment. [ABSTRACT FROM AUTHOR]

There is much promise in the use of immunotherapy for the treatment of cancer. approaches such as those using anti-bodies or adoptive cell transfer can mediate complete tumor regression in a proportion of patients. However, the tumor microenvironment can inhibit immune responses leading to ineffective or suboptimal responses of tumors to immunotherapy in the majority of cases. As our knowledge of the tumor microenvironment increases, many strategies are emerging for changing the immunosuppressive nature of the tumor toward a microenvironment able to support immunity. These strategies aim to enhance the ability of immunotherapies to initiate effective immune responses able to destroy tumors. In this article, we review approaches that use immunomodulators specifically to modify the tumor microenvironment, and their use in combination with other immune-based strategies for cancer therapy. [ABSTRACT FROM AUTHOR]

The success of checkpoint immunotherapy has created optimism that cancer may be curable. However, not all patients respond, resistance is common and many patients relapse owing to immune escape. We demonstrate that HDAC inhibition not only decreases the trafficking of myeloid-derived suppressor cells (MDSCs) into tumors but also potentiates tumor-associated macrophages (TAMs) to specify anti-tumoral phenotype and bolster T cells activation within the tumor microenvironment (TME). [ABSTRACT FROM AUTHOR]

Inflammation, which is now recognized as an hallmark of cancer, is intimately linked to the reactivity of stromal ibroblasts. Accumulating evidence indicate that cancer-associated ibroblasts not only drive the epithelial-mesenchymal transition and metabolically sustain the growth of cancer cells, but also engage in a reciprocal relationship with M2 macrophages that dramatically boost malignancy. [ABSTRACT FROM AUTHOR]

It has been recently recognized that the tumor microenvironment (TME) is an essential factor that defines the efficiency of chemotherapy. The local TME, consisting of immune cells with diverse phenotypes and functions, can strongly modulate the response to chemotherapy. Tumor-associated macrophages (TAMs) that display pronounced heterogeneity and phenotypic plasticity are the major innate immune component in the microenvironment of solid tumors. In our review, we elucidate the complex role of TAMs in the progression of different types of solid tumors, summarize the current knowledge about the effects of different anticancer chemotherapeutic agents on monocytes/macrophages, and describe the mechanisms of chemotherapy resistance mediated by TAMs. [ABSTRACT FROM AUTHOR]

Primary diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) is an aggressive disease with a poor prognosis. The status of the tumor immune microenvironment in CNS-DLBCL remains unclear. We investigated the prognostic implications of tumor-associated macrophages (TAMs), regulatory T-cells (Tregs), and indoleamine 2,3-dioxygenase (IDO)+ cells in primary CNS-DLBCL (n = 114) by immunohistochemical analysis. The numbers of tumor-infiltrating immune cells, including CD68+ TAMs, CD163+ or CD204+ M2 macrophages, FOXP3+ Tregs, and IDO+ cells were all significantly lower in CNS-DLBCL versus systemic DLBCL (n = 165; all P < 0.001), but with little difference in the ratio of CD163+/CD68+ or CD204+/CD68+ cells. An increase in CD68+ cell numbers was significantly associated with prolonged progression-free survival (PFS) and overall survival in patients with CNS-DLBCL (P = 0.004 and 0.021, respectively). In contrast, an increase in CD204+ cell numbers or a higher ratio of CD204+/CD68+ cells was related to a shorter PFS (P = 0.020 and 0.063, respectively). An increase in IDO+ cell numbers was associated with a significantly longer PFS (P = 0.019). In combination, the status of low IDO+ cell numbers combined with low CD68+ cell numbers, high CD204+ cell numbers, or a high CD204+/CD68+ cell ratio all predicted poor PFS in multivariate analyses. This study showed that an increase in CD204+ cell numbers, suggestive of M2 macrophages, was associated with poor clinical outcome in CNS-DLBCL, whereas increased CD68+ or IDO+ cell numbers were related to a favorable prognosis. The analysis of tumor-infiltrating immune cells could help in predicting the prognosis of CNS-DLBCL patients and determining therapeutic strategies targeting tumor microenvironment. [ABSTRACT FROM AUTHOR]

Interleukin-10 (IL10) is an immune regulatory cytokine. Single nucleotide polymorphisms (SNPs) in IL10 promoter have been associated with prognosis in adult classical Hodgkin lymphoma (cHL). We analyzed IL10 SNPs −1082 and −592 in respect of therapy response, gene expression and tumor microenvironment (TME) composition in 98 pediatric patients with cHL. As confirmatory results, we found that −1082AA/AG; −592CC genotypes and ATA haplotype were associated with unfavourable prognosis: Progression-free survival (PFS) was shorter in −1082AA+AG (72.2%) than in GG patients (100%) (P = 0.024), and in −592AA (50%) and AC (74.2%) vs. CC patients (87.0%) (P = 0.009). In multivariate analysis, the −592CC genotype and the ATA haplotype retained prognostic impact (HR: 0.41, 95% CI 0.2-0.86; P = 0.018, and HR: 3.06 95% CI 1.03-9.12; P = 0.044, respectively). Our analysis further led to some new observations, namely: (1) Low IL10 mRNA expression was associated with −1082GG genotype (P = 0.014); (2) IL10 promoter polymorphisms influence TME composition;−1082GG/−592CC carriers showed low numbers of infiltrating cells expressing MAF transcription factor (20 vs. 78 and 49 vs. 108 cells/mm2, respectively; P< 0.05); while ATA haplotype (high expression) associated with high numbers of MAF+ cells (P = 0.005). Specifically, −1082GG patients exhibited low percentages of CD68+MAF+ (M2-like) intratumoral macrophages (15.04% vs. 47.26%, P = 0.017). Considering ours as an independent validation cohort, our results give support to the clinical importance of IL10 polymorphisms in the full spectrum of cHL, and advance the concept of genetic control of microenvironment composition as a basis for susceptibility and therapeutic response. [ABSTRACT FROM AUTHOR]

Pancreatic Ductal Adenocarcinoma (PDA) is characterized by a complex tumor microenvironment that supports its progression, aggressiveness and resistance to therapies. The delicate interplay between cancer and immune cells creates the conditions for PDA development, particularly due to the functional suppression of T cell anti-tumor effector activity. However, some of the mechanisms involved in this process are still poorly understood. In this study, we analyze whether the functional and epigenetic profile of T cells that infiltrate PDA is modulated by the microenvironment, and in particular by tumor-associated macrophages (TAMs). CD4 and CD8 T cells obtained from mice orthotopically injected with syngeneic PDA cells, and untreated or treated with Trabectedin, a cytotoxic drug that specifically targets TAMs, were sorted and analyzed by flow cytometry and characterized for their epigenetic profile. Assessment of cytokine production and the epigenetic profile of genes coding for IL10, T-bet and PD1 revealed that T cells that infiltrated PDA displayed activatedIl10promoter and repressedT-betactivity, in agreement with their regulatory phenotype (IL10high/IFNγlow, PD1high). By contrast, in Trabectedin-treated mice, PDA-infiltrating T cells displayed repressedIl10andPdcd1and activatedT-betpromoter activity, in accordance with their anti-tumor effector phenotype (IL10low/IFNγhigh), indicating a key role of TAMs in orchestrating functions of PDA-infiltrating T cells by modulating their epigenetic profile towards a pro-tumoral phenotype. These results suggest the targeting of TAMs as an efficient strategy to obtain an appropriate T cell anti-tumor immune response and open new potential combinations for PDA treatment. [ABSTRACT FROM AUTHOR]

The immune contexture, a composition of the tumor microenvironment, plays multiple important roles in cancer stem cell (CSC) and epithelial–mesenchymal transition (EMT), and hence critically influences tumor initiation, progression and patient outcome. Tumor-associated macrophages (TAMs) are abundant in immune contexture, however their roles in CSC, EMT and prognosis of colorectal cancer (CRC) have not been elucidated. In 419 colorectal carcinomas, immune cell types (CD68+macrophages, CD3+, CD4+or CD8+T lymphocytes, CD20+B lymphocytes), EMT markers (E-cadherin and Snail) as well as the stem cell marker (CD44v6) were detected in tumor center (TC) and tumor invasive front (TF) respectively by immunohistochemistry. Tumor buds, that represent EMT phenotype, were also counted. It was found CD68+macrophages were the most infiltrating immune cells in CRC. By correlation analysis, more CD68+TFmacrophages were associated with more CD44v6 expression (p < 0.001), lower SnailTFexpression (p = 0.08) and fewer tumor buds (p < 0.001). More CD68+TFmacrophages were significantly related to more CD3+TFT lymphocytes (p = 0.002), CD8+TFT lymphocytes (p < 0.001) and CD20+TFB lymphocytes counts (p = 0.004). Strong CD68+TFmacrophages infiltration also predicted long term overall survival. CRC patients with more tumor buds had worse survival. However, strong CD68+TFmacrophages infiltration could reverse the unfavorable results since patients with more tumor buds but increasing CD68+TFmacrophages infiltration had the favorable outcome, similar to lower tumor buds groups. This study provided direct morphological evidence that tumor-associated macrophages in the invasive front play critical roles in fighting with the unfavorable results of tumor buds, thus resulting favorable outcomes for CRC patients. [ABSTRACT FROM AUTHOR]

Tumor microenvironment (TME) contains a variety of infiltrating immune cells. Among them, tumor-associated macrophages (TAMs) and their alternative activation contribute greatly to the progression of tumors. The mechanisms governing macrophage polarization in the TME are unclear. Here, we show that in TAMs or macrophages under tumor-conditioned medium treatment, the expression of transcription factor EB (TFEB) is reduced and more of the TFEB protein is in an inactive cytosolic form. Transforming growth factor (TGF)-β is identified as a main driving force for the reduced TFEB expression and activity in TAMs via activating ERK signaling. TFEB interference in macrophages significantly enhanced their alternative activation, with reduced expression of MHC-II and co-stimulatory molecule CD80, decreased ability to activate T cells, and increased ability to attract tumor cells. When co-inoculated with tumor cells, macrophages with TFEB knockdown significantly enhanced tumor growth with increased infiltration of M2-like macrophages, reduced infiltration of CD8+T cells, and enhanced angiogenesis in the tumors. Mechanistic studies revealed that TFEB downregulation resulted in macrophage M2 polarization through reducing SOCS3 production and enhancing STAT3 activation. We further demonstrate that the activation of TFEB by hydroxypropyl-β-cyclodextrin in macrophages suppressed their M2 polarization and tumor-promoting capacity, and that macrophage-specific TFEB overexpression inhibited breast tumor growth in mice. Therefore, our data suggest that TFEB plays critical roles in macrophage polarization, and the downregulation of TFEB expression and activation is an integral part of tumor-induced immune editing in the TME. This study provides a rationale for a new cancer treatment strategy by modulating macrophage polarization through activating TFEB. [ABSTRACT FROM PUBLISHER]

Chondrosarcoma (CHS) is a rare bone malignancy characterized by its resistance to conventional systemic and radiation therapies. Whether immunotherapy targeting immune checkpoints may be active in these tumors remains unknown. To explore the role of the immune system in this tumor, we analyzed the immune environment of chondrosarcomas both in human sample, and in a syngeneic rat model, and tested the contribution of T lymphocytes and macrophages in chondrosarcoma progression. Immunohistochemical stainings were performed on human chondrosarcoma samples and on Swarm rat chondrosarcoma (SRC) model. Selective immunodepletion assays were performed in SRC to evaluate immune population's involvement in tumor progression. In human and rat chondrosarcoma, immune infiltrates composed of lymphocytes and macrophages were identified in the peritumoral area. Immune infiltrates composition was found correlated with tumors characteristics and evolution (grade, invasiveness and size). In SRC, selective depletion of T lymphocytes resulted in an accelerated growth rates, whereas depletion of CD163+macrophages slowed down tumor progression. Splenocytes isolated from CHS-bearing SRC showed a specific cytotoxicity directed against chondrosarcoma cells (27%), which significantly decreased in CD3-depleted SRC (11%). The immune environment contributes to CHS progression in both human and animal models, suggesting that immunomodulatory approaches could be tested in bone chondrosarcoma. [ABSTRACT FROM AUTHOR]

In experimental mouse models of cancer, increasingly compelling evidence point toward a contribution of tumor associated macrophages (TAM) to tumor lymphangiogenesis. Corresponding experimental observations in human cancer remain scarce although lymphatic metastasis is widely recognized as a predominant route for tumor spread. We previously showed that, in malignant tumors of untreated breast cancer (BC) patients, TIE-2-expressing monocytes (TEM) are highly proangiogenic immunosuppressive cells and that TIE-2 and VEGFR signaling pathways drive TEM immunosuppressive function. We report here that, in human BC, TEM express the canonical lymphatic markers LYVE-1, Podoplanin, VEGFR-3 and PROX-1. Critically, both TEM acquisition of lymphatic markers and insertion into lymphatic vessels were observed in tumors but not in adjacent non-neoplastic tissues, suggesting that the tumor microenvironment shapes both TEM phenotype and spatial distribution. We assessed the lymphangiogenic activity of TEM isolated from dissociated primary breast tumorsin vitroandin vivousing endothelial cells (EC) sprouting assay and corneal vascularization assay, respectively. We show that, in addition to their known hemangiogenic function, TEM isolated from breast tumor display a lymphangiogenic activity. Importantly, TIE-2 and VEGFR pathways display variable contributions to TEM angiogenic and lymphangiogenic activities across BC patients; however, combination of TIE-2 and VEGFR kinase inhibitors abrogated these activities and overcame inter-patient variability. These results highlight the direct contribution of tumor TEM to the breast tumor lymphatic network and suggest a combined use of TIE-2 and VEGFR kinase inhibitors as a therapeutic approach to block hem- and lymphangiogenesis in BC. [ABSTRACT FROM AUTHOR]

Advanced stages of cancer often involve multiple tumors in different locations in the body. These tumors are associated with a microenvironment that can influence tumor responses to immunotherapy. Whether tumors and their disparate microenvironment can interact together at distance in a multiple tumor setting, through a form of cross-talk, and affect their responses to immunotherapy has never been described. Our study investigated the cross-talk between two tumors with disparate microenvironments in a mouse model. We demonstrated that immunosuppressive visceral tumors could influence distant subcutaneous (SC) tumors to render them resistant to immunotherapy. We observed distinct modifications in the SC tumor microenvironment following cross-talk with kidney tumors that exhibit a type-2 macrophage-related immunosuppressive microenvironment. Indeed, when a concomitant kidney tumor was present in the mouse, the SC tumors were highly infiltrated with M2 macrophages and had a reduced T cell and NK cell effector immune profile. Finally, blocking the M2-associated chemokine CCL2 or depleting macrophages, significantly improved the effect of immunotherapy on growth of SC tumors in the presence of concomitant kidney tumors. This work emphasizes the potential negative influence that a tumor, with a strong immunosuppressive microenvironment, can exert on distant tumors that would normally be treatment-responsive. This report may lead to a new vision of the prioritization in the treatment of advanced metastatic cancer. [ABSTRACT FROM PUBLISHER]

A number of studies point to an aberrant differentiation and accumulation of CD14+PD-L1+M2-macrophage-like cells in the microenvironment of cervical cancer, which promote immunosuppressive conditions and are associated with tumor invasion, angiogenesis and metastasis. Therapeutic targeting of these macrophages may tip the balance in favor of antitumor immunity. Cervical cancer is the fourth most common cancer among women worldwide and is caused by a persistent infection and subsequent integration of high-risk types of the human papillomavirus. Continuous expression of the viral oncoproteins E6 and E7 has been shown essential to maintain the transformed state of infected keratinocytes. As these non-self oncoproteins are immunogenic, cervical cancer requires a highly immune suppressed tumor microenvironment to metastasize through lymphovascular space invasion (LVSI) to the pelvic tumor-draining lymph nodes (TDLN). Unraveling the mechanisms underlying this immune suppression may uncover novel therapeutic targets aimed at loco-regional control of cervical cancer. [ABSTRACT FROM AUTHOR]

Early stage growth of intracranial B16F10 tumors is reduced by 87% in myeloid-specific NG2 null (Mac-NG2ko) mice and by 77% in pericyte-specific NG2 null (PC-NG2ko) mice, demonstrating the importance of the NG2 proteoglycan in each of these stromal compartments. In both genotypes, loss of pericyte-endothelial cell interaction results in numerous structural defects in tumor blood vessels, including decreased formation of endothelial cell junctions and decreased assembly of the vascular basal lamina. All vascular deficits are larger in Mac-NG2ko mice than in PC-NG2ko mice, correlating with the greater decrease in pericyte-endothelial cell interaction in Mac-NG2ko animals. Accordingly, tumor vessels in Mac-NG2ko mice have a smaller diameter, lower degree of patency, and higher degree of leakiness than tumor vessels in PC-NG2ko mice, leading to less efficient tumor blood flow and to increased intratumoral hypoxia. While reduced pericyte interaction with endothelial cells in PC-NG2ko mice is caused by loss of NG2-dependent pericyte activation of β1 integrin signaling in endothelial cells, reduced pericyte-endothelial cell interaction in Mac-NG2ko mice is due to a 90% reduction in NG2-dependent macrophage recruitment to tumors. The absence of a macrophage-derived signal(s) in Mac-NG2ko mice results in the loss of pericyte ability to associate with endothelial cells, possibly due to reduced expression of N-cadherin by both pericytes and endothelial cells. [ABSTRACT FROM PUBLISHER]