Metabolic inhibition induces pyroptosis in uveal melanoma.

Few treatment options are available for metastatic uveal melanoma (UM) patients. Although the bispecific tebentafusp is FDA-approved, immunotherapy has largely failed, likely given the poorly immunogenic nature of UM. Treatment options that improve the recognition of UM by the immune system may be key to reducing disease burden.

In Science Journals.

Highlights from the family of journals.

In Science Journals.

Highlights from the family of journals.

In Science Journals.

Highlights from the family of journals.

In Science Journals.

Highlights from the family of journals.

In Science Journals.

Highlights from the family of journals.

In Science Journals.

Highlights from the family of journals.

In Science Journals.

Highlights from the family of journals.

In Science Journals.

Highlights from the family of journals.

In Science Journals.

Highlights from the family of journals.

In Science Journals.

[Figure: see text].

In Science Journals.

Highlights from the family of journals.

In Science Journals.

Highlights from the family of journals.

In Science Journals.

Highlights from the family of journals.

Mechanisms of Antiviral Cytotoxic CD4 T Cell Differentiation.

Cytotoxic CD4 T lymphocytes (CD4-CTL) are important in antiviral immunity. For example, we have previously shown that in mice, CD4-CTL are important to control ectromelia virus (ECTV) infection. How viral infections induce CD4-CTL responses remains incompletely understood.

Activation of CD8 T Cells Contributes to Antitumor Effects of CDK4/6 Inhibitors plus MEK Inhibitors.

Concurrent MEK and CDK4/6 inhibition shows promise in clinical trials for patients with advanced-stage mutant / solid tumors. The effects of CDK4/6 inhibitor (CDK4/6i) in combination with BRAF/MEK-targeting agents on the tumor immune microenvironment are unclear, especially in melanoma, for which immune checkpoint inhibitors are effective in approximately 50% of patients. Here, we show that patients progressing on CDK4/6i/MEK pathway inhibitor combinations exhibit T-cell exclusion.

FOXD3 Regulates VISTA Expression in Melanoma.

Immune checkpoint inhibitors have improved patient survival in melanoma, but the innate resistance of many patients necessitates the investigation of alternative immune targets. Many immune checkpoint proteins lack proper characterization, including V-domain Ig suppressor of T cell activation (VISTA). VISTA expression on immune cells can suppress T cell activity; however, few studies have investigated its expression and regulation in cancer cells.

Targeting BRD/BET proteins inhibits adaptive kinome upregulation and enhances the effects of BRAF/MEK inhibitors in melanoma.

Background: BRAF-mutant melanoma patients respond to BRAF inhibitors and MEK inhibitors (BRAFi/MEKi), but drug-tolerant cells persist, which may seed disease progression. Adaptive activation of receptor tyrosine kinases (RTKs) has been associated with melanoma cell drug tolerance following targeted therapy. While co-targeting individual RTKs can enhance the efficacy of BRAFi/MEKi effects, it remains unclear how to broadly target multiple RTKs to achieve more durable tumour growth inhibition.

Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis.

Combinations of BRAF inhibitors and MEK inhibitors (BRAFi + MEKi) are FDA-approved to treat -mutant melanoma. Efficacy of BRAFi + MEKi associates with cancer cell death and alterations in the tumor immune microenvironment; however, the links are poorly understood. We show that BRAFi + MEKi caused durable melanoma regression in an immune-mediated manner.

PLX3397 inhibits the accumulation of intra-tumoral macrophages and improves bromodomain and extra-terminal inhibitor efficacy in melanoma.

Bromodomain and extra-terminal inhibitors (BETi) delay tumor growth, in part, through tumor cell intrinsic alterations and initiation of anti-tumor CD8+ T-cell responses. By contrast, BETi effects on pro-tumoral immune responses remain unclear. Here, we show that the next-generation BETi, PLX51107, delayed tumor growth to differing degrees in Braf V600E melanoma syngeneic mouse models.

ERK1/2 Reporter Predictively Models Response and Resistance to Combined BRAF and MEK Inhibitors in Melanoma.

Combined BRAF and MEK inhibition is a standard of care in patients with advanced BRAF-mutant melanoma, but acquired resistance remains a challenge that limits response durability. Here, we quantitated ERK1/2 activity and tumor response associated with resistance to combined BRAF and MEK inhibition in mutant BRAF xenografts. We found that ERK1/2 pathway reactivation preceded the growth of resistant tumors.

The next-generation BET inhibitor, PLX51107, delays melanoma growth in a CD8-mediated manner.

Epigenetic agents such as bromodomain and extra-terminal region inhibitors (BETi) slow tumor growth via tumor intrinsic alterations; however, their effects on antitumor immunity remain unclear. A recent advance is the development of next-generation BETi that are potent and display a favorable half-life. Here, we tested the BETi, PLX51107, for immune-based effects on tumor growth in BRAF V600E melanoma syngeneic models.

Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation.

Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis by forming pores in the plasma membrane. Here we show that GSDME-N also permeabilizes the mitochondrial membrane, releasing cytochrome c and activating the apoptosome. Cytochrome c release and caspase-3 activation in response to intrinsic and extrinsic apoptotic stimuli are significantly reduced in GSDME-deficient cells comparing with wild type cells.

CADM1 is a TWIST1-regulated suppressor of invasion and survival.

Metastatic cancer remains a clinical challenge; however, patients diagnosed prior to metastatic dissemination have a good prognosis. The transcription factor, TWIST1 has been implicated in enhancing the migration and invasion steps within the metastatic cascade, but the range of TWIST1-regulated targets is poorly described. In this study, we performed expression profiling to identify the TWIST1-regulated transcriptome of melanoma cells.