Targeting BRAF in an Inducible Murine Model of Melanoma

Hooijkaas, Anna I.; Gadiot, Jules; Valk, Martin van der; Mooi, Wolter J.; Blank, Christian U.

doi:10.1016/j.ajpath.2012.06.002

Cited by 60 publications

(88 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data with the Braf CA Tyr-creER T2 Pten fl/fl mice are the first to our knowledge to demonstrate any single-agent activity of an immunotherapy in this de novo melanomagenesis model. In concert with our findings, when treating similar transgenic mice with anti-CTLA-4, Hooijkaas et al have reported no significant therapeutic activity (44). By contrast, they report a small decrease in the proportion of various intratumoral lymphocytes 2 and 21 days after PLX4720, but it is not clear in this study how the mock control tumors relate to the PLX4720-treated tumors (in size or days treatment).…”

Section: Discussioncontrasting

confidence: 49%

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors

Knight¹,

Ngiow²,

Li³

et al. 2013

J. Clin. Invest.

254

188

View full text Add to dashboard Cite

The BRAF mutant, BRAF V600E , is expressed in nearly half of melanomas, and oral BRAF inhibitors induce substantial tumor regression in patients with BRAF V600E metastatic melanoma. The inhibitors are believed to work primarily by inhibiting BRAF V600E -induced oncogenic MAPK signaling; however, some patients treated with BRAF inhibitors exhibit increased tumor immune infiltration, suggesting that a combination of BRAF inhibitors and immunotherapy may be beneficial. We used two relatively resistant variants of Braf V600E -driven mouse melanoma (SM1 and SM1WT1) and melanoma-prone mice to determine the role of host immunity in type I BRAF inhibitor PLX4720 antitumor activity. We found that PLX4720 treatment downregulated tumor Ccl2 gene expression and decreased tumor CCL2 expression in both Braf V600E mouse melanoma transplants and in de novo melanomas in a manner that was coincident with reduced tumor growth. While PLX4720 did not directly increase tumor immunogenicity, analysis of SM1 tumor-infiltrating leukocytes in PLX4720-treated mice demonstrated a robust increase in CD8 + T/FoxP3 + CD4 + T cell ratio and NK cells. Combination therapy with PLX4720 and anti-CCL2 or agonistic anti-CD137 antibodies demonstrated significant antitumor activity in mouse transplant and de novo tumorigenesis models. These data elucidate a role for host CCR2 in the mechanism of action of type I BRAF inhibitors and support the therapeutic potential of combining BRAF inhibitors with immunotherapy.

show abstract

Section: Discussioncontrasting

confidence: 49%

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors

Knight¹,

Ngiow²,

Li³

et al. 2013

J. Clin. Invest.

254

188

View full text Add to dashboard Cite

show abstract

“…S1M and S1N). Because of the leakiness of the inducible Tyr-Cre system (15), spontaneous tumors appeared more frequently on mice transplanted with Ikkβ Mye Δ/Δ than Ikkβ WT marrow (Supplementary Fig. S1O and S1P).…”

Section: Resultsmentioning

confidence: 99%

Myeloid IKKβ Promotes Antitumor Immunity by Modulating CCL11 and the Innate Immune Response

et al. 2014

View full text Add to dashboard Cite

Myeloid cells are capable of promoting or eradicating tumor cells and the nodal functions that contribute to their different roles are still obscure. Here, we show that mice with myeloid-specific genetic loss of the NF-κB pathway regulatory kinase IKKβ exhibit more rapid growth of cutaneous and lung melanoma tumors. In a BRAFV600E/PTEN−/− allograft model, IKKβ loss in macrophages reduced recruitment of myeloid cells into the tumor, lowered expression of MHC class II molecules, and enhanced production of the chemokine CCL11, thereby negatively regulating dendritic-cell maturation. Elevated serum and tissue levels of CCL11 mediated suppression of dendritic-cell differentiation/maturation within the tumor microenvironment, skewing it toward a Th2 immune response and impairing CD8+ T cell–mediated tumor cell lysis. Depleting macrophages or CD8+ T cells in mice with wild-type IKKβ myeloid cells enhanced tumor growth, where the myeloid cell response was used to mediate antitumor immunity against melanoma tumors (with less dependency on a CD8+ T-cell response). In contrast, myeloid cells deficient in IKKβ were compromised in tumor cell lysis, based on their reduced ability to phagocytize and digest tumor cells. Thus, mice with continuous IKKβ signaling in myeloid-lineage cells (IKKβCA) exhibited enhanced antitumor immunity and reduced melanoma outgrowth. Collectively, our results illuminate new mechanisms through which NF-κB signaling in myeloid cells promotes innate tumor surveillance.

show abstract

“…Although inducible models of BRAF V600E have been described and used to test therapeutic agents [39,45,46], variability in tumor expression of current inducible transgenic BRAF models and random development of spontaneous tumors have precluded widespread use of these transgenic models up to this point. Development of spontaneous tumors has been attributed in part to leakiness in the inducible Cre/lox promoter designed to control induction of melanomagenesis [45]. However, despite the drawbacks of the current transgenic models, B16 tumors also have limitations.…”

Section: Discussionmentioning

confidence: 99%

Type I-polarized BRAF-pulsed dendritic cells induce antigen-specific CD8+ T cells that impact BRAF-mutant murine melanoma

Cintolo

Datta

et al. 2016

Melanoma Research

View full text Add to dashboard Cite

Existing therapies targeting the mutated BRAF oncodriver (BRAF(V600E)) successfully treat melanoma but are susceptible to resistance. This study assessed the potential of a dendritic cell-based BRAF(V600E) vaccine for the treatment of BRAF(V600E)-mutant melanoma. Type 1-polarized dendritic cells (DC1) pulsed with affinity-modified BRAF(V600E) peptide were administered to C57Bl/6 mice both before (prevention) and twice weekly after (treatment) the development of established tumor with B16 melanoma transfected to express BRAF(V600E) (B16(V600E)). The efficacy of the BRAF(V600E)-pulsed DC1 vaccine was corroborated in a novel transplantable BRAF(V600E)-mutant murine melanoma model (BRAF(V600E-/+); PTEN(-/-); CDK2NA(-/-)). Three-dimensional tumor measurements and survival were determined. Induction of BRAF(V600E)-specific CD8(+) T-cell responses after brief in-vitro sensitization was assessed by interferon-γ enzyme-linked immunosorbent assay and/or enzyme-linked immunospot. Mice receiving BRAF(V600E)-pulsed DC1 vaccines before B16(V600E) tumor challenge demonstrated increased tumor-doubling times (P<0.001) and improved survival (P=0.0186) compared with those that received ovalbumin (control)-pulsed DC1 vaccines. In mice bearing established B16(V600E) tumors (mean 32 mm(3)), BRAF-pulsed DC1 vaccines delayed tumor growth (P<0.001) and improved survival (P=0.0008), compared with untreated mice. Likewise, in mice bearing BRAF(V600E-/+); PTEN(-/-); CDK2NA(-/-) tumors, compared with controls, BRAF-DC1 vaccination recapitulated these effects by delaying tumor growth (P<0.001) and improving survival (P=0.002). Vaccination elicited specific CD8(+) T-cell recognition of BRAF(V600E)-pulsed antigen-presenting cells (P<0.05), as well as BRAF(V600E)-expressing cancer cells (P<0.001), measured by interferon-γ release in vitro. BRAF-(V600E)pulsed DC1 vaccines induce oncogene-specific CD8(+) T-cell immune responses that impact tumor growth and survival in preclinical models of BRAF(V600E)-mutant melanoma. Exploration of BRAF(V600E)-targeted vaccines, in combination with BRAF-targeted therapies and checkpoint inhibitors, is warranted.

show abstract

Targeting BRAF in an Inducible Murine Model of Melanoma

Cited by 60 publications

References 48 publications

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors

Myeloid IKKβ Promotes Antitumor Immunity by Modulating CCL11 and the Innate Immune Response

Type I-polarized BRAF-pulsed dendritic cells induce antigen-specific CD8+ T cells that impact BRAF-mutant murine melanoma

Contact Info

Product

Resources

About