Targeting tumor-associated macrophages in cancer therapy and understanding their complexity.
Ontology highlight
ABSTRACT:
SUBMITTER: Cannarile MA
PROVIDER: S-EPMC4292237 | biostudies-other | 2014 Oct
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Immune-responsive gene 1 (IRG1) is a mitochondrial aconitate decarboxylase and can produce the immunomodulatory metabolite itaconic acid (ITA). However, its role in modulating the function of tumor-associated macrophages (TAMs) remains elusive. Here, we show that IRG1 is expressed in TAMs in human tumors and mouse models of cancer. Tumor cells induce Irg1 expression in macrophages which dampens the inflammatory response and restricts M1-like TAM polarization. In contrast, Irg1-deficent macrophages acquire more proinflammatory M1-like features, promote immunogenic antigen presentation, and enhance cytotoxic T cell infiltration into tumor sites. Consequently, Irg1 deficiency suppresses the growth of mouse syngeneic tumors, including melanoma, colorectal cancer, breast cancer, and pancreatic cancer. Irg1-deficient macrophages not only dictate the tumoricidal effect but enhance the efficacy of anti-PD(L)1 immunotherapy. In conclusion, our data identify IRG1 as a myeloid immune check point gene and foster the development of genetic or pharmacologic targeting of IRG1 for skewing macrophages toward an anti-tumor phenotype to treat a broad spectrum of cancer.
2023-05-01 | GSE210845 | GEO
Project description:The tumor microenvironment is replete with cells that evolve with and provide support to tumor cells during the transition to malignancy. The hijacking of the immune system in the pancreatic tumor microenvironment is suggested to contribute to the failure to date to produce significant improvements in pancreatic cancer survival by various chemotherapeutics. Regulatory T cells, myeloid derived suppressor cells, and fibroblasts, all of which constitute a complex ecology microenvironment, can suppress CD8+ T cells and NK cells, thus inhibiting effector immune responses. Tumor-associated macrophages (TAM) are versatile immune cells that can express different functional programs in response to stimuli in tumor microenvironment at different stages of pancreatic cancer development. TAM have been implicated in suppression of anti-tumorigenic immune responses, promotion of cancer cell proliferation, stimulation of tumor angiogenesis and extracellular matrix breakdown, and subsequent enhancement of tumor invasion and metastasis. Many emerging agents that have demonstrated efficacy in combating other types of tumors via modulation of macrophages in tumor microenvironments are, however, only marginally studied for pancreatic cancer prevention and treatment. A better understanding of the paradoxical roles of TAM in pancreatic cancer may pave the way to novel preventive and therapeutic approaches. Here we give an overview of the recruitment and differentiation of macrophages, TAM and pancreatic cancer progression and prognosis, as well as the potential preventive and therapeutic targets that interact with TAM for pancreatic cancer prevention and treatment.
| S-EPMC5226617 | biostudies-other
Project description:Tumor-associated macrophages (TAMs) represent the most abundant leukocyte population in most solid tumors and are greatly influenced by the tumor microenvironment. More importantly, these macrophages can promote tumor growth and metastasis through interactions with other cell populations within the tumor milieu and have been associated with poor outcomes in multiple tumors. In this review, we examine how the tumor microenvironment facilitates the polarization of TAMs. Additionally, we evaluate the mechanisms by which TAMs promote tumor angiogenesis, induce tumor invasion and metastasis, enhance chemotherapeutic resistance, and foster immune evasion. Lastly, we focus on therapeutic strategies that target TAMs in the treatments of cancer, including reducing monocyte recruitment, depleting or reprogramming TAMs, and targeting inhibitory molecules to increase TAM-mediated phagocytosis.
| S-EPMC8582510 | biostudies-literature
Project description:Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest antiangiogenic therapy-induced hypoxia can induce tumor "stemness" as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor-associated macrophages (TAM). As such, TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin. G5-methotrexate (G5-MTX) nanoparticles deplete TAMs in both solid tumor and ascites models of ovarian cancer. As a therapeutic agent, these nanoparticles are more effective than cisplatin. Importantly, these nanoparticles could (i) overcome resistance to antiangiogenic therapy, (ii) prevent antiangiogenic therapy-induced increases in cancer stem-like cells in both murine and human tumor cell models, (iii) prevent antiangiogenic therapy-induced increases in VEGF-C, and (iv) prevent antiangiogenic therapy-induced BRCA1 gene expression. Combined, this work strongly supports the development of TAM-targeted nanoparticle therapy. Mol Cancer Ther; 17(1); 96-106. ©2017 AACR.
| S-EPMC5752569 | biostudies-literature
Project description:Macrophages are phagocytic cells that play a broad role in maintaining body homeostasis and defense against foreign pathogens; whereas tumor-associated macrophages (TAMs) support tumor growth and metastasis by promoting cancer cell proliferation and invasion, immunosuppression, and angiogenesis, which is closely related to the poor prognosis in almost all solid tumors. Hence, deep-insight knowledge into TAMs can provide an opportunity to discover more effective strategies for cancer therapeutics. So far, a large number of therapeutic agents targeting TAMs are in clinical trials. In this review, we introduce an extensive overview about macrophages and macrophage-targeting agents.
| S-EPMC7674960 | biostudies-literature
Project description:Macrophages, an important class of innate immune cells that maintain body homeostasis and ward off foreign pathogens, exhibit a high degree of plasticity and play a supportive role in different tissues and organs. Thus, dysfunction of macrophages may contribute to advancement of several diseases, including cancer. Macrophages within the tumor microenvironment are known as tumor-associated macrophages (TAMs), which typically promote cancer cell initiation and proliferation, accelerate angiogenesis, and tame anti-tumor immunity to promote tumor progression and metastasis. Massive infiltration of TAMs or enrichment of TAM-related markers usually indicates cancer progression and a poor prognosis, and consequently tumor immunotherapies targeting TAMs have gained significant attention. Here, we review the interaction between TAMs and cancer cells, discuss the origin, differentiation and phenotype of TAMs, and highlight the role of TAMs in pro-cancer functions such as tumor initiation and development, invasive metastasis, and immunosuppression. Finally, we review therapies targeting TAMs, which are very promising therapeutic strategies for malignant tumors.
| S-EPMC8222665 | biostudies-literature
Project description:Clinical and experimental models have identified macrophages as potential targets for cancer therapy, however, the nature of macrophage differentiation and function in the context of malignant disease remain largely uncharacterized. This commentary provides the author's perspective on the recently published article "The cellular and molecular origin of tumor-associated macrophages," which demonstrated that tumor growth elicits a specific macrophage differentiation pathway.
| S-EPMC4292439 | biostudies-other
Project description:Tumor-associated macrophages (TAMs) are the most abundant population type of tumor-infiltrating immune cells found in the tumor microenvironment (TME), and are evolutionarily associated with microvessel density in tumor tissues. TAMs can be broadly divided into M1-like and M2-like TAMs, which demonstrate antitumor and pro-tumor activity in the TME, respectively. Studies have indicated that: i) The predominate presence of M2-like TAMs in the TME can result in tumor immunosuppression and chemoresistance; ii) the ratio of M1-like to M2-like TAMs in the TME is positively correlated with better long-term prognosis of patients with cancer; iii) epigenetic silencing, preventing the secretion of M1-like TAM-associated molecules, is an important immune evasion mechanism during tumor progression; and iv) the transformation from M2-like to M1-like TAMs following exposure to specific conditions can result in tumor regression. The present study discusses the molecular events underlying the recruitment of macrophages and their polarization into M1-like or M2-like TAMs, and their differential roles in angiogenesis, angiostasis, invasion, metastasis and immune activity in the TME. This insight may inform the improved design of TAM-targeted cancer immunotherapy. Some of these therapeutic strategies show promising effects; however, challenges remain.
| S-EPMC7500051 | biostudies-literature
Project description:The current treatment strategies in advanced malignancies remain limited. Notably, immunotherapies have raised hope for a successful control of these advanced diseases, but their therapeutic responses are suboptimal and vary considerably among individuals. Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and are often correlated with poor prognosis and therapy resistance, including immunotherapies. Thus, a deeper understanding of the complex roles of TAMs in immunotherapy regulation could provide new insight into the TME. Furthermore, targeting of TAMs is an emerging field of interest due to the hope that these strategies will synergize with current immunotherapies. In this review, we summarize recent studies investigating the involvement of TAMs in immune checkpoint inhibition, tumor vaccines and adoptive cell transfer therapies, and discuss the therapeutic potential of targeting TAMs as an adjuvant therapy in tumor immunotherapies.
| S-EPMC7900181 | biostudies-literature
Project description:Tumor-associated macrophages (TAMs) are associated with tumor progression and metastasis. Here, we demonstrate for the first time that legumain, a member of the asparaginyl endopeptidase family functioning as a stress protein, overexpressed by TAMs, provides an ideal target molecule. In fact, a legumain-based DNA vaccine served as a tool to prove this point, as it induced a robust CD8+ T cell response against TAMs, which dramatically reduced their density in tumor tissues and resulted in a marked decrease in proangiogenic factors released by TAMs such as TGF-beta, TNF-alpha, MMP-9, and VEGF. This, in turn, led to a suppression of both tumor angiogenesis and tumor growth and metastasis. Importantly, the success of this strategy was demonstrated in murine models of metastatic breast, colon, and non-small cell lung cancers, where 75% of vaccinated mice survived lethal tumor cell challenges and 62% were completely free of metastases. In conclusion, decreasing the number of TAMs in the tumor stroma effectively altered the tumor microenvironment involved in tumor angiogenesis and progression to markedly suppress tumor growth and metastasis. Gaining better insights into the mechanisms required for an effective intervention in tumor growth and metastasis may ultimately lead to new therapeutic targets and better anticancer strategies.
| S-EPMC1513049 | biostudies-literature