The Immune Microenvironment Confers Resistance to MAPK Pathway Inhibitors through Macrophage-Derived TNFα

Smith, Michael P.; Sánchez-Laorden, Berta; O’Brien, Kate; Brunton, Holly; Ferguson, Jennifer; Young, Helen; Dhomen, Nathalie; Flaherty, Keith T.; Frederick, Dennie T.; Cooper, Zachary A.; Wargo, Jennifer A.; Marais, Richard; Wellbrock, Claudia

doi:10.1158/2159-8290.cd-13-1007

Cited by 189 publications

(206 citation statements)

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“…In addition, emerging therapies for the treatment of melanomas, such as anti-CTLA4 (50), and BRAF V600E inhibitors (7,8), are associated with CD8 þ T-cell immune response and TNF production, even in patients with disease progression. Macrophage-derived TNF is important for BRAF V600E melanoma growth in vivo and confers resistance to MAPK pathway inhibitors (16). Whether a combination of anti-TNF and emerging therapies may exert a clinical benefit by enhancing CD8 þ T-cell-dependent immune response toward melanoma remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Similar data have been obtained by injecting anti-TNF-neutralizing antibodies (14) or soluble TNF-R1 (15), indicating that TNF blockade may represent a useful strategy to prevent melanoma metastasis. A recent study showed that TNF deficiency can delay tumor growth in a spontaneous mouse model of BRAF V600E melanoma (16). In humans, whereas different case reports have documented the occurrence of melanoma in patients with autoimmune disorders treated with anti-TNF, recent meta-analyses did not confirm the association of anti-TNF treatments and an increased melanoma incidence (17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

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Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma

et al. 2015

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“…This resistance mechanism can be overcome by combining MEK inhibitors with an inhibitor of NF-κB signaling to prevent TAM accumulation and TNF secretion in tumors. Interestingly, TNF expression is independent of the state of TAM polarization in this model, as all cultured macrophages expressed TNF regardless of the stimuli used in vitro to skew their polarization [106]. By contrast, TAM polarization may be important for the response to targeted therapies in other cancer types and can even result in adverse effects.…”

Section: Innate Immune Cellsmentioning

confidence: 80%

“…In mice bearing melanoma cell lines derived from Braf V600E ;Tyr::CreERT2 tumors, the release of TNF by TAMs protects tumors from MEK inhibitor-induced cell death [106]. This resistance mechanism can be overcome by combining MEK inhibitors with an inhibitor of NF-κB signaling to prevent TAM accumulation and TNF secretion in tumors.…”

Section: Innate Immune Cellsmentioning

confidence: 99%

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

125

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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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“…Although less characterized than tumor macrophages and IL-17-producing T cells 12,13 , neutrophils are also emerging as important players in the pathophysiology of cancer. [14][15][16] Neutrophils are the most abundant leukocytes and serve as essential effector cells in the first line of host defense against invading microorganisms.…”

Section: Introductionmentioning

confidence: 99%

Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma

He¹,

Peng²,

Huang³

et al. 2016

OncoImmunology

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Inflammation is a component of tumor progression mechanisms. Neutrophils are a common inflammatory infiltrate in many tumors, but their regulation and functions in neoplasia are not understood. Here, we showed, in detailed studies of c-Met molecule in 225 untreated patients with hepatocellular carcinoma (HCC), that high infiltration of neutrophils in HCC tissues determined malignant cell c-Met-associated clinical outcome of patients. High infiltration of neutrophils in HCCs determined malignant cell c-Metassociated clinical outcome of patients. Neutrophils were enriched predominantly in invading tumor edge of HCCs; the accumulated neutrophils were the major source of c-Met ligand HGF in HCCs. Exposure to HCC environments resulted in neutrophil activation and the following HGF production. Inhibiting the activities of Erk1/2, p38, and NF-kB, but not the phosphorylation of AKT or JNK, successfully attenuated the neutrophil HGF production induced by HCC environments. Further investigation revealed that GM-CSF was an important determinant in malignant cell-elicited neutrophil HGF production in vitro and in vivo. Moreover, we demonstrated that tumor neutrophils, via HGF/c-Met interaction, actively enhanced the metastasis of malignant cells in vitro and in vivo. These data provide direct evidence supporting the critical role of neutrophils in human tumor progression and reveal a fine-tuned collaborative action between cancer cells and immune cells in tumor milieu, which reroutes the immune activation into a tumorpromoting direction.

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The Immune Microenvironment Confers Resistance to MAPK Pathway Inhibitors through Macrophage-Derived TNFα

Cited by 189 publications

References 50 publications

Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma

Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma

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