Natural Killer Cells Are Essential for the Ability of BRAF Inhibitors to Control BRAFV600E-Mutant Metastatic Melanoma

Andrade, Lucas Ferrari de; Ngiow, Shin Foong; Stannard, Kimberley; Rusakiewicz, Sylvie; Kalimutho, Murugan; Khanna, Kum Kum; Tey, Siok-Keen; Takeda, Kazuyoshi; Zitvogel, Laurence; Martinet, Ludovic; Smyth, Mark J.

doi:10.1158/0008-5472.can-14-1339

Cited by 96 publications

(80 citation statements)

References 37 publications

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“…4T1.2 and E0771 mammary carcinomas were obtained from Dr. Robin Anderson at the Peter MacCallum Cancer Centre (2004 and 2014, respectively). RM-1 prostate carcinoma cell lines were maintained, injected, and monitored as described previously (4,(19)(20)(21). Human breast cancer cell lines MDA-MB-231, SUM159PT, and MDA-MB-468 were all purchased from the ATCC (2014)(2015), and MDA-MB-231-derived spontaneous metastatic cell line, MDA-MB-231-HM-LNm5, was obtained from Dr.…”

Section: Methodsmentioning

confidence: 99%

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

et al. 2016

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Adenosine plays an important role in inflammation and tumor development, progression, and responses to therapy. We show that an adenosine 2B receptor inhibitor (A2BRi) decreases both experimental and spontaneous metastasis and combines with chemotherapy or immune checkpoint inhibitors in mouse models of melanoma and triple-negative breast cancer (TNBC) metastasis. Decreased metastasis upon A2BR inhibition is independent of host A2BR and lymphocytes and myeloid cells. Knockdown of A2BR on mouse and human cancer cells reduces their metastasis in vivo and decreases their viability and colony-forming ability, while transiently delaying cell-cycle arrest in vitro. The prometastatic activity of adenosine is partly tumor A2BR dependent and independent of host A2BR expression. In humans, TNBC cell lines express higher A2BR than luminal and Her2 þ breast cancer cell lines, and high expression of A2BR is associated with worse prognosis in TNBC. Collectively, high A2BR on mouse and human tumors promotes cancer metastasis and is an ideal candidate for therapeutic intervention. Cancer Res; 76(15); 4372-82. Ó2016 AACR.

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Section: Methodsmentioning

confidence: 99%

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

et al. 2016

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“…We and others have recently demonstrated that (a) NK cells selectively target freshly explanted tumor cells, (b) activation and frequency are related to the clinical outcome of melanoma and (c) specific NK cell subsets found in tumorinfiltrated lymph nodes of melanoma patients can eliminate autologous tumor cells. [24][25][26][27][28][29] We hypothesized that the in-depth characterization of T and NK cells in the peripheral blood of melanoma patients before CONTACT Paolo A. Ascierto p.ascierto@istitutotumori.na.it, paolo.ascierto@gmail.com Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale," Via Mariano Semmola, 80131 Napoli, Italy; Ennio Carbone ennio.carbone@ki.se Tumor Immunology and Immunopathology Laboratory, Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, Campus -Germaneto, 88100 Catanzaro, Italy.…”

Section: Introductionmentioning

confidence: 99%

IL-15, TIM-3 and NK cells subsets predict responsiveness to anti-CTLA-4 treatment in melanoma patients

et al. 2017

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Despite the success of immune checkpoint blockade in melanoma, the majority of patients do not respond. We hypothesized that the T and NK cell subset frequencies and expression levels of their receptors may predict responses and clinical outcome of anti-CTLA-4 treatment. We thus characterized the NK and T cell phenotype, as well as serum levels of several cytokines in 67 melanoma patients recruited in Italy and Sweden, using samples drawn prior to and during treatment. Survival correlated with low expression of the inhibitory receptor TIM-3 on circulating T and NK cells prior to and during treatment and with the increased frequency of mature circulating NK cells (defined as CD3 ¡ CD56 dim CD16 C ) during treatment. Survival also correlated with low levels of IL-15 in the serum. Functional experiments in vitro demonstrated that sustained exposure to IL-15 enhanced the expression of PD-1 and TIM-3 on both T and NK cells, indicating a causative link between high IL-15 levels and enhanced expression of TIM-3 on these cells. Receptor blockade of TIM-3 improved NK cell-mediated elimination of melanoma metastasis cell lines in vitro. These observations may lead to the development of novel biomarkers to predict patient response to checkpoint blockade treatment. They also suggest that induction of additional checkpoints is a possibility that needs to be considered when treating melanoma patients with IL-15.

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“…In experimental melanoma metastasis models, NK cells mediate the anti-tumor effects of a BRAF inhibitor, while CD4 + and CD8 + T cells are dispensable [123]. By contrast, CD8 + T cells are required for the response of BRAF inhibitors in transplantable melanoma models [124,125], CD4 + T cells, but not CD8 + T cells, mediate tumor clearance following BRAF inhibitor treatment of spontaneous melanomas in a GEMM [126] (Braf V600E ;Pten F/F ;Tyr::CreERT2 mice [127]).…”

Section: Adaptive Immune Cellsmentioning

confidence: 99%

“…TAMs resident in pancreatic tumors suppress CD8 + T cell functions, and targeting TAMs via anti-CSF1R together with gemcitabine decreases liver metastasis through reactivation of CD8 + T cells [29]. Experiments carried out in melanoma metastasis models have shown that the BRAF inhibitor, PLX4720, and the cKIT inhibitor, imatinib, are effective against lung metastases via an NK cell-dependent mechanism [123,128]. In addition, other mechanistic studies have identified several putative targets that may be effective at combating metastasis, including IL17-producing γδ T cells [49] and prometastatic neutrophils [48,49].…”

Section: Glossary Boxmentioning

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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Natural Killer Cells Are Essential for the Ability of BRAF Inhibitors to Control BRAFV600E-Mutant Metastatic Melanoma

Cited by 96 publications

References 37 publications

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

IL-15, TIM-3 and NK cells subsets predict responsiveness to anti-CTLA-4 treatment in melanoma patients

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

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