KIT oncogene inhibition drives intratumoral macrophage M2 polarization

Cavnar, Michael J.; Zeng, Shan; Kim, Teresa S.; Sorenson, Eric C.; Ocuin, Lee M.; Balachandran, Vinod P.; Seifert, Adrian M.; Greer, Jonathan B.; Popow, Rachel; Crawley, Megan H.; Cohen, Noah A.; Green, Benjamin L.; Rossi, Ferdinand; Besmer, Peter; Antonescu, Cristina R.; DeMatteo, Ronald P.

doi:10.1084/jem.20130875

Cited by 116 publications

(125 citation statements)

References 56 publications

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“…TAMs and MDSCs exert their immunosuppressive effects in an antigen-NOTCH signaling (22) or lactic acid-stabilized HIF-1α (36). M1-like TAMs are detectable in early-stage cancers as well as in regressing cancers and necrotic areas of growing tumors (40). Furthermore, monocytes isolated from the blood of patients with renal cell carcinoma (RCC) simultaneously express both tumor-suppressing genes, such as TNF and IL1A, and tumor-promoting genes, such as VEGFA, MMP9, and HIF1A, a mixed profile that was confirmed in macrophages of RCC specimens (41).…”

Section: Myeloid Cells and Cancer Promotionmentioning

confidence: 99%

Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages

Ugel¹,

Sanctis²,

Mandruzzato

et al. 2015

Journal of Clinical Investigation

453

405

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Section: Myeloid Cells and Cancer Promotionmentioning

confidence: 99%

Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages

Ugel¹,

Sanctis²,

Mandruzzato

et al. 2015

Journal of Clinical Investigation

453

405

View full text Add to dashboard Cite

“…[3][4][5] While M1 macrophages produce pro-inflammatory mediators such as tumor necrosis factor-a (TNF-a), IL-6, IL-12, IL-23, and NO, and have a role in killing intracellular microorganisms, M2 macrophages produce anti-inflammatory mediators such as IL-4, IL-5, IL-10, and IL-13, and are important in atopic disease, parasite response, and tumor progression. [6][7][8] The diverse polarized phenotypes of M1-M2 macrophages can, to some extent, be dynamically reversed in vitro and in vivo. 1 Moreover, pathology is frequently associated with dynamic changes of macrophage polarization, with M1 macrophages implicated in initiating and sustaining acute inflammation and M2 macrophages associated with resolution or smoldering chronic inflammation.…”

mentioning

confidence: 99%

Polycomb-mediated loss of microRNA let-7c determines inflammatory macrophage polarization via PAK1-dependent NF-κB pathway

Zhang

Liu

et al. 2014

Cell Death Differ

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Serine/threonine kinase family members p21-activated kinases (PAKs) are important regulators of cytoskeletal remodeling and cell motility in mononuclear phagocytic system, but their role in macrophage differentiation and polarization remains obscure. We have shown here that inflammatory stimuli induced PAK1 overexpression in human and murine macrophages. Elevated expression of PAK1 contributed to macrophage M1 polarization and lipopolysaccharide (LPS)-induced endotoxin shock. We further observed that epigenetic loss of microRNA let-7c due to enhancer of zeste homolog 2 (EZH2) upregulation determined PAK1 elevation and inflammatory phenotype in M1 macrophages. EZH2/let-7c/PAK1 axis promotes macrophage M1 polarization via NIK-IKK-NF-jB signaling. Moreover, pharmacological and genetic ablation with EZH2/let-7c/PAK1 axis blunted inflammatory phenotype in M1 macrophages. Critically, either myeloid-restricted PAK1 deletion (PAK1 Lyz2cre ) or pharmacological and genetic ablation with EZH2/let-7c/PAK1 signal resulted in resistance to LPS-induced endotoxin shock via blunting macrophage M1 polarization. PAK1, therefore, is an essential controller of inflammatory macrophage polarization, regulating immune responses against pathogenic stimuli.

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“…By contrast, TAM polarization may be important for the response to targeted therapies in other cancer types and can even result in adverse effects. Imatinib treatment of tumorbearing Kit V558/+ mice -which carry a gain-of-function point mutation on one allele of the Kit receptor gene predisposing them to spontaneous gastrointestinal stromal tumor (GIST) development [107] -has been shown to repolarize TAMs from their normal anti-tumorigenic, T cell-stimulating phenotype to a more pro-tumorigenic phenotype [108]. However, the consequence of TAM skewing by imatinib, whether this is beneficial or detrimental for tumor progression, remains untested.…”

Section: Innate Immune Cellsmentioning

confidence: 99%

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

121

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SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

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KIT oncogene inhibition drives intratumoral macrophage M2 polarization

Abstract: Imatinib reduces tumor cell KIT signaling and causes tumor cell apoptosis, which drives TAMs to shift from M1- to M2-like in mouse and human GIST.

Cited by 116 publications

References 56 publications

Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages

Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages

Polycomb-mediated loss of microRNA let-7c determines inflammatory macrophage polarization via PAK1-dependent NF-κB pathway

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

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