Aspartate signalling drives lung metastasis via alternative translation.

Lung metastases occur in up to 54% of patients with metastatic tumours. Contributing factors to this high frequency include the physical properties of the pulmonary system and a less oxidative environment that may favour the survival of cancer cells. Moreover, secreted factors from primary tumours alter immune cells and the extracellular matrix of the lung, creating a permissive pre-metastatic environment primed for the arriving cancer cells.

Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.

Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation.

Influence of adjuvant therapies on organ-specific recurrence of cutaneous melanoma: A multicenter study on 1383 patients of the prospective DeCOG registry ADOReg.

This study investigated whether adjuvant treatments in stage III cutaneous melanoma (CM) influenced patterns of recurrence. Patients with primary (n = 1033) or relapsed CM (n = 350) who received adjuvant therapies with Nivolumab (N), Pembrolizumab (P), or Dabrafenib and Trametinib (D + T) were extracted from the prospective multicenter real-world skin cancer registry ADOReg. Endpoints were progression-free survival (PFS), distant metastasis-free survival (DMFS), organ-specific DMFS, and overall survival (OS).

The Interplay between Metabolic Adaptations and Diet in Cancer Immunotherapy.

Over the past decade, cancer immunotherapy has significantly advanced through the introduction of immune checkpoint inhibitors and the augmentation of adoptive cell transfer to enhance the innate cancer defense mechanisms. Despite these remarkable achievements, some cancers exhibit resistance to immunotherapy, with limited patient responsiveness and development of therapy resistance. Metabolic adaptations in both immune cells and cancer cells have emerged as central contributors to immunotherapy resistance.

T antigen-specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD-1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag-specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag-reactive CD8+ T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the oncoproteins, covering 33 class I haplotypes.

Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study.

JCO Pembrolizumab adjuvant therapy was shown to significantly improve recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB or IIC melanoma in earlier analyses of the randomized, double-blind, phase III KEYNOTE-716 study (ClinicalTrials.gov identifier: NCT03553836). We report results of the protocol-specified final analysis of DMFS for KEYNOTE-716.

Leptin receptor cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor.

The bone marrow contains peripheral nerves that promote haematopoietic regeneration after irradiation or chemotherapy (myeloablation), but little is known about how this is regulated. Here we found that nerve growth factor (NGF) produced by leptin receptor-expressing (LepR) stromal cells is required to maintain nerve fibres in adult bone marrow. In nerveless bone marrow, steady-state haematopoiesis was normal but haematopoietic and vascular regeneration were impaired after myeloablation.

Treatment management for -mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG.

Background: Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, V600-mutant (mut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM.

The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity.

The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization.

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs.

Advancements in melanoma cancer metastasis models.

Metastatic melanoma is a complex and deadly disease. Due to its complexity, the development of novel therapeutic strategies to inhibit metastatic melanoma remains an outstanding challenge. Our ability to study metastasis is advanced with the development of in vitro and in vivo models that better mimic the different steps of the metastatic cascade beginning from primary tumor initiation to final metastatic seeding.

Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma.

Purpose: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI).

Experimental Design: Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts.

Emerging metabolomic tools to study cancer metastasis.

Metastasis is responsible for 90% of deaths in patients with cancer. Understanding the role of metabolism during metastasis has been limited by the development of robust and sensitive technologies that capture metabolic processes in metastasizing cancer cells. We discuss the current technologies available to study (i) metabolism in primary and metastatic cancer cells and (ii) metabolic interactions between cancer cells and the tumor microenvironment (TME) at different stages of the metastatic cascade.

Compartmentalized metabolism supports midgestation mammalian development.

Mammalian embryogenesis requires rapid growth and proper metabolic regulation. Midgestation features increasing oxygen and nutrient availability concomitant with fetal organ development. Understanding how metabolism supports development requires approaches to observe metabolism directly in model organisms in utero.

Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial.

Background: Pembrolizumab prolongs progression-free and overall survival among patients with advanced melanoma and recurrence-free survival in resected stage III disease. KEYNOTE-716 assessed pembrolizumab as adjuvant therapy in patients with completely resected, high-risk, stage II melanoma. We report results from the planned first and second interim analyses for recurrence-free survival.

TMB and Inflammatory Gene Expression Associated with Clinical Outcomes following Immunotherapy in Advanced Melanoma.

Outcomes for patients with melanoma have improved over the past decade as a result of the development and FDA approval of immunotherapies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death ligand 1 (PD-L1). However, these therapies do not benefit all patients, and an area of intensive research investigation is identifying biomarkers that can predict which patients are most likely to benefit from them. Here, we report exploratory analyses of the associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and mutation status with tumor response, progression-free survival, and overall survival in patients with advanced melanoma treated as part of the CheckMate 066 and 067 phase III clinical trials evaluating immuno-oncology therapies.

Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study.

Background: Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers.

Methods: ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment).

Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors.

Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects.

Patients And Methods: The study comprised of dose escalation and dose expansion cohorts.

Indirect treatment comparison of nivolumab versus placebo for the adjuvant treatment of melanoma.

Introduction: Until recently, adjuvant treatment options for stage III and IV resectable melanoma have been limited. Patients were often managed through routine surveillance. The phase III randomised controlled trial (RCT) CheckMate 238 (238) demonstrated the safety and efficacy of nivolumab as an adjuvant treatment for melanoma in patients with stage IIIB/C or IV disease (American Joint Committee on Cancer [AJCC], 7th edition) versus ipilimumab.

Baseline T1 hyperintense and diffusion-restricted lesions are not linked to prolonged survival in bevacizumab-treated glioblastoma patients of the GLARIUS trial.

Purpose: The phase II GLARIUS trial assigned patients with newly diagnosed, O-6-methylguanine-DNA methyltransferase promoter non-methylated glioblastoma to experimental bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ). To identify subpopulations with a particularly favorable course, we assessed the prognostic potential of magnetic resonance imaging (MRI) markers before treatment onset.

Methods: MRIs at baseline (before treatment onset) were analyzed for T1-hyperintense and diffusion-restricted lesions; as well as the presence of both hyperintense and diffusion-restricted (double positive) lesions.