Featured
-
-
Article
| Open AccessMolecular patterns of resistance to immune checkpoint blockade in melanoma
A large fraction of patients with melanoma still does not benefit from immune checkpoint blockade, associated with both primary and acquired resistance. Here the authors report genetic and immunological patterns of resistance in patients with melanoma after progression on anti-CTLA4 or anti-PD1 monotherapy.
- Martin Lauss
- , Bengt Phung
- & Göran Jönsson
-
Article
| Open AccessStroma-infiltrating T cell spatiotypes define immunotherapy outcomes in adolescent and young adult patients with melanoma
Therapeutic resistance to immune checkpoint inhibitor treatment is incompletely understood in adolescent and young-adult (AYA) patients with melanoma. Here, the authors demonstrate that AYA patients exhibit a unique stroma-infiltrating T cell immunogenomic profile compared with adults, which impacts on their responsiveness to immunotherapy.
- Xinyu Bai
- , Grace H. Attrill
- & Camelia Quek
-
Article
| Open AccessMultipeptide vaccines for melanoma in the adjuvant setting: long-term survival outcomes and post-hoc analysis of a randomized phase II trial
Peptide-based cancer vaccines require epitopes for both CD8+ and CD4+ T cells. Here the authors report the long-term outcomes of a randomized phase II trial (NCT00118274) in patients with melanoma designed to evaluate a class I MHC-restricted peptide vaccine plus one of two “helper” peptide preparations to stimulate CD4+ T cells, either non-specific help or melanoma-specific help.
- Emily K. Ninmer
- , Hong Zhu
- & Craig L. Slingluff Jr
-
Article
| Open AccessMi-2β promotes immune evasion in melanoma by activating EZH2 methylation
Mi-2β is an enzyme of the chromodomain helicase DNA family with roles in chromatin assembly, genomic stability and gene repression. Here the authors report that Mi-2β promotes immune evasion by activating EZH2 methylation and that loss of Mi-2β or its inhibition promote anti-tumor immune responses in preclinical melanoma models.
- Cang Li
- , Zhengyu Wang
- & Rutao Cui
-
Article
| Open AccessAdjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial
Immunotherapy using dendritic cell (DC)-based vaccination has been exploited in the clinic for cancer treatment. Here the authors report the results of a randomized, placebo-controlled, phase 3 trial of adjuvant blood-derived DC cell-based therapy in patients with stage IIIB and IIIC melanoma.
- Kalijn F. Bol
- , Gerty Schreibelt
- & I. Jolanda M. de Vries
-
Article
| Open AccessNeoadjuvant cobimetinib and atezolizumab with or without vemurafenib for high-risk operable Stage III melanoma: the Phase II NeoACTIVATE trial
Immunotherapy with immune checkpoint inhibitors and targeted therapy with BRAF and MEK inhibition have revolutionized the treatment of melanoma. Here the authors report the results of a phase II trial of neoadjuvant cobimetinib (MEK inhibitor) and atezolizumab (anti-PD-L1) with or without the BRAF inhibitor vemurafenib in patients with resectable Stage III melanoma.
- Tina J. Hieken
- , Garth D. Nelson
- & Matthew S. Block
-
Article
| Open AccessCAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes
A main challenge for the use of CAR-T in solid tumours is the identification of surface proteins as feasible targets. Here, the authors show TYRP1 as a target for CAR-T cell therapy in preclinical models of cutaneous, acral and uveal melanoma.
- Sameeha Jilani
- , Justin D. Saco
- & Cristina Puig-Saus
-
Article
| Open AccessAndrogen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation
Mechanisms underlying sex associated differences in the role of androgen receptor (AR) in melanoma are unclear. Here the authors show that androgen-activated AR transcriptionally upregulates fucosyltransferase 4, which fucosylates L1CAM and promotes melanoma invasiveness by disrupting adherens junctions.
- Qian Liu
- , Emma Adhikari
- & Eric K. Lau
-
Article
| Open AccessTumor reactive γδ T cells contribute to a complete response to PD-1 blockade in a Merkel cell carcinoma patient
Immune checkpoint blockade cancer therapy has been designed to enable tumor killing by conventional αβ T cells. Here authors show that in a Merkel cell carcinoma patient showing complete response to anti-PD-1 treatment, innate-like γδ T cells that specifically recognize the tumor cells expand, and likely contribute to therapeutic success.
- Scott C. Lien
- , Dalam Ly
- & Pamela S. Ohashi
-
Article
| Open AccessANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation
The transcriptional program controlling the activation of cancer-associated fibroblasts (CAFs) remains to be elucidated. Here, the authors identify ANKRD1 as a mesenchymal-specific driver of CAF activation under negative direct control of androgen receptor, triggering AP-1 transcription factor complex activation.
- Luigi Mazzeo
- , Soumitra Ghosh
- & G. Paolo Dotto
-
Article
| Open AccessPhosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma
Upregulation of GLI1 of has previously been reported in sonic hedgehog (SHH) driven medulloblastoma and basal cell carcinoma (BCC). Here, the authors find that SHH-inactivation of p38 results in stabilization of the transcription factor GLI1 via dephosphorylation at Ser937, resulting in expression of SHH genes and presenting a potential therapy strategy for medulloblastoma and BCC.
- Ling-Hui Zeng
- , Chao Tang
- & Jirong Wang
-
Article
| Open AccessIn-situ-sprayed therapeutic hydrogel for oxygen-actuated Janus regulation of postsurgical tumor recurrence/metastasis and wound healing
Surgery is a primary therapeutic modality for treating melanoma, but it is challenging to tackle tumor recurrence/metastasis and postsurgical wounds. Here the authors report a sprayable hydrogel capable of long-lasting and controllable oxygen supply for preventing tumor recurrence/metastasis and simultaneously promoting wound healing during the postsurgical treatment of melanoma.
- Shuiling Chen
- , Yang Luo
- & Shaobing Zhou
-
Article
| Open AccessA wearable electrostimulation-augmented ionic-gel photothermal patch doped with MXene for skin tumor treatment
A wearable biological patch capable of producing multiple responses to light and electricity without interfering with daily activities is desired for skin cancer treatment but remains elusive. Herein, the authors report a skin-mountable and dual-responsive electrothermal patch for melanoma treatment by the co-therapy of photothermal and electrical stimulations.
- Xingkai Ju
- , Jiao Kong
- & Yongdong Jin
-
Article
| Open AccessMHC-I upregulation safeguards neoplastic T cells in the skin against NK cell-mediated eradication in mycosis fungoides
Defective immune responses have been reported in cutaneous T-cell lymphoma (CTCL). Here the authors show that in patients with mycosis fungoides, the most common CTCL, malignant T cells upregulate MHC-I as a mechanism to evade NK-mediated immunity.
- Yun-Tsan Chang
- , Pacôme Prompsy
- & Emmanuella Guenova
-
Article
| Open AccessCell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity
It has been reported that the circadian clock regulator Bmal1 can modulate tumorigenesis. Here the authors show that ectopic expression of Bmal1 promotes an immune resistant mesenchymal melanoma cell state associated with increased AP-1 activity.
- Xue Zhang
- , Shishir M. Pant
- & Chi V. Dang
-
Article
| Open AccessSequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial
SECOMBIT was a clinical trial testing different sequences of immunotherapy (ipilimumab plus nivolumab) and targeted therapy (encorafenib plus binimetinib) for untreated BRAF-mutated metastatic melanoma. Here the authors report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy, and preliminary biomarkers evaluation.
- Paolo A. Ascierto
- , Milena Casula
- & Giuseppe Palmieri
-
Article
| Open AccessDelineating the early dissemination mechanisms of acral melanoma by integrating single-cell and spatial transcriptomic analyses
Acral melanoma (AM) is a rare melanoma subtype with unique features, where lymph node metastasis is closely associated with clinical outcomes. Here, the authors use single-cell and spatial transcriptomics to analyse early dissemination, tumour microenvironment, and heterogeneity in AM, and infer metabolic shifts with therapeutic implications.
- Chuanyuan Wei
- , Wei Sun
- & Jianying Gu
-
Article
| Open AccessHDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis
The drivers of melanoma brain metastases (MBM) remain poorly understood. Here, the authors identify stress-induced HDAC8 activity as the driver of a neural crest-stem cell like transcriptional state that leads to MBM, and explore the molecular mechanism that drives this transition.
- Michael F. Emmons
- , Richard L. Bennett
- & Keiran S. M. Smalley
-
Article
| Open AccessImmuno-metabolic dendritic cell vaccine signatures associate with overall survival in vaccinated melanoma patients
Efficacy of dendritic cell (DC)-based vaccines remains unsatisfactory. Here the authors analyse the transcriptomic and immune-metabolic profiles of DCs from patients enrolled in a DC vaccine trial in late-stage melanoma, suggesting that the metabolic profile of DC is associated with the immunostimulatory potential of the cancer vaccine.
- Juraj Adamik
- , Paul V. Munson
- & Lisa H. Butterfield
-
Article
| Open AccessDisrupting cellular memory to overcome drug resistance
Identifying memory and state switching in single cells remains elusive. Here, the authors develop a method, scMemorySeq, by combining cell barcoding and scRNA-seq and apply it to human melanoma cells to track lineages as they switch states between a drug-susceptible state and a state primed for drug resistance.
- Guillaume Harmange
- , Raúl A. Reyes Hueros
- & Sydney M. Shaffer
-
Article
| Open AccessTracing cancer evolution and heterogeneity using Hi-C
It is challenging to analyse chromosomal rearrangements in heterogeneous solid cancers. Here the authors present HiDENSEC, a method to jointly infer absolute copy number, ploidy, tumor purity and large-scale rearrangements from Hi-C data. The increased statistical power afforded by joint inference enables novel insights into cancer genome evolution.
- Dan Daniel Erdmann-Pham
- , Sanjit Singh Batra
- & Dirk Hockemeyer
-
Article
| Open AccessAndrogen receptor is a determinant of melanoma targeted drug resistance
BRAF inhibitor response in melanoma is variable, and BRAF mutated patients often relapse. Here, the authors show that androgen receptor expression is linked to BRAF inhibitor response, and is a potential therapeutic target to increase efficacy.
- Anastasia Samarkina
- , Markus Kirolos Youssef
- & Gian Paolo Dotto
-
Article
| Open AccessUncovering the complex relationship between balding, testosterone and skin cancers in men
Male-pattern baldness (MPB) is related to dysregulation of androgens. Here, authors show that MPB (but not androgens) is associated with skin cancer risk, particularly in the scalp region, suggesting that sun exposure, rather than androgens, is the main driver.
- Jue-Sheng Ong
- , Mathias Seviiri
- & Matthew H. Law
-
Article
| Open AccessAcetylation reprograms MITF target selectivity and residence time
The microphthalmia-associated transcription factor MITF is a lineage-survival oncogene that plays a crucial role in melanocyte development and melanoma. Here, the authors reveal that MITF has a very long chromatin-bound half-life, and that MITF target selectivity is regulated by K206 acetylation, a residue linked to Waardenburg syndrome.
- Pakavarin Louphrasitthiphol
- , Alessia Loffreda
- & Colin R. Goding
-
Article
| Open AccessGuadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial
The NIBIT-M4 trial was designed to assess the safety, biological and clinical activity of anti-CTLA4 ipilimumab with the DNA hypomethylating agent guadecitabine in advanced melanoma patients. Here the authors report the five-year follow-up results of the trial and an integrated multi-omics analysis of pre- and on-treatment tumor biopsies.
- Teresa Maria Rosaria Noviello
- , Anna Maria Di Giacomo
- & Michele Ceccarelli
-
Article
| Open AccessFunctionally distinct cancer-associated fibroblast subpopulations establish a tumor promoting environment in squamous cell carcinoma
During the progression of cutaneous squamous cell carcinoma (cSCC), dermal fibroblasts become activated into cancer-associated fibroblasts (CAFs) which are pro-tumorigenic. Here, using single-cell RNA sequencing of patients’ samples at different stages of cSCC progression, the authors identify two main CAF subsets and deduce their potential functions using bioinformatics.
- Sabrina Schütz
- , Llorenç Solé-Boldo
- & Frank Lyko
-
Article
| Open AccessDriver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression
The process by which actinic keratosis differentiates to malignant invasive cutaneous squamous cell carcinoma is unclear. Here, the authors use RNA-seq to illustrate a disease continuum between the two states, and use in vivo models to confirm the role of Tgfbr2, Trp53, and Notch1 in this process.
- Peter Bailey
- , Rachel A. Ridgway
- & Gareth J. Inman
-
Article
| Open AccessB cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma
B cells are playing an active role in shaping the tumour immune microenvironment and the anti-tumour immune response in melanomas. Here authors show that intra-tumoral B cells are aberrantly activated and produce antibodies that are potentially autoreactive.
- Silvia Crescioli
- , Isabel Correa
- & Sophia N. Karagiannis
-
Article
| Open AccessEpigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas
Melanoma phenotypic switching contributes to targeted BRAF treatment resistance. Here the authors identify a subset of BRAF treatment-resistant melanomas with suppressed PGC1a expression that are sensitive to HMGCR inhibitors.
- Jiaxin Liang
- , Deyang Yu
- & Pere Puigserver
-
Article
| Open AccessLipid droplets are a metabolic vulnerability in melanoma
Lipid droplets are a dynamic organelle found in a variety of cell types, most prominently in adipocytes. Here, the authors find in zebrafish and human cells that lipid droplets are enriched in a subset of melanoma cells that promote cancer formation and growth.
- Dianne Lumaquin-Yin
- , Emily Montal
- & Richard M. White
-
Article
| Open AccessSkin basal cell carcinomas assemble a pro-tumorigenic spatially organized and self-propagating Trem2+ myeloid niche
Tumor microenvironment elements can influence tumor state, including in skin basal cell carcinomas. Here the authors show that spatially organized and self-propagating TREM2+ tumor associated macrophages promote Ly6D- tumor cell proliferation via secretion of oncostatin M.
- Daniel Haensel
- , Bence Daniel
- & Anthony E. Oro
-
Article
| Open AccessContributions of replicative and translesion DNA polymerases to mutagenic bypass of canonical and atypical UV photoproducts
Vandenberg et al. identify differing roles of yeast DNA polymerases during accurate and mutagenic synthesis past common and rare ultraviolet light photoproducts. Similar mechanisms may contribute to driver mutations causing skin cancer in humans.
- Brittany N. Vandenberg
- , Marian F. Laughery
- & Steven A. Roberts
-
Article
| Open AccessGenomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients
Xeroderma pigmentosum (XP) is a rare genetic disorder that is associated with a higher risk of skin cancer. Here, the authors analyse the genomes of skin cancers from patients across five different XP groups, revealing genetic and molecular factors related to the mutational profile and UV-related mutagenesis in XP.
- Andrey A. Yurchenko
- , Fatemeh Rajabi
- & Sergey I. Nikolaev
-
Article
| Open AccessIdentification of CircRNA signature associated with tumor immune infiltration to predict therapeutic efficacy of immunotherapy
Circular RNAs are known to be linked to cancer regulation. Here, the authors identify a circular RNA signature associated with immune checkpoint response in melanoma.
- Yu Dong
- , Qian Gao
- & Youqiong Ye
-
Article
| Open AccessAnti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4
IgE antibodies targeting cancer antigens can be used for immunotherapy. Here the authors present an IgE antibody targeting the melanoma-associated antigen, chondroitin sulphate proteoglycan 4, that recognises human melanoma, stimulates tumour cell cytotoxicity, and restricts tumour growth in humanised mouse models.
- Jitesh Chauhan
- , Melanie Grandits
- & Heather J. Bax
-
Article
| Open AccessAn epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma
Melanocytes can de-differentiate into neural crest cell (NCC)- like states during metastatic melanoma progression. Here the authors compare DNA methylation profiles of NCCs and melanocytes, as well as primary and metastatic patient tissues and identify that DNA methylation changes of NR2F2 isoform 2 influence cell state transitions and melanoma metastatic spread.
- Veronica Davalos
- , Claudia D. Lovell
- & Eva Hernando
-
Article
| Open AccessEpigenetic state determines the in vivo efficacy of STING agonist therapy
STING agonists have shown limited efficacy in early-phase clinical trials despite promising pre-clinical data. This study shows the potential clinical relevance of the use of combination STING agonists and demethylating agent therapies to induce the expression of STING.
- Rana Falahat
- , Anders Berglund
- & James J. Mulé
-
Article
| Open AccessThe molecular and functional landscape of resistance to immune checkpoint blockade in melanoma
Immunotherapy resistance is common among melanoma patients. Here, the authors identify three resistance mechanism subtypes across tumor-derived cell lines and matched samples and highlight antigen presentation disruption as a key mediator of resistance.
- Su Yin Lim
- , Elena Shklovskaya
- & Helen Rizos
-
Article
| Open AccessTowards routine chromosome-scale haplotype-resolved reconstruction in cancer genomics
The precise inference of structural variants (SVs) requires suitable sequencing technologies and computational tools. Here, in order to analyse SVs with haplotype resolution, the author applies high-resolution long-read sequencing and long-range Hi-C to a melanoma cell line and develops an efficient graph-based computational framework, pstools.
- Shilpa Garg
-
Article
| Open AccessThe TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma
TINCR encodes a p53-regulated ubiquitin-like microprotein expressed in stratified epithelia. Tincr loss promotes UVB-induced skin carcinogenesis in mice and deletions and mutations in human squamous cell carcinoma support a tumor suppressor role.
- Lucia Morgado-Palacin
- , Jessie A. Brown
- & Adolfo A. Ferrando
-
Article
| Open AccessLoss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage
Thyroid hormones have an important role in fostering tumour progression, however their upstream regulators are less clear. Here, the authors identify the thyroid hormone activating enzyme type 2 deiodinase as a p53 target gene and demonstrate its contribution to tumour progression in p53 mutant squamous cell carcinoma.
- Annarita Nappi
- , Caterina Miro
- & Monica Dentice
-
Article
| Open AccessThe ULK3 kinase is a determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome
The identification of kinases that control epigenetic mechanisms in squamous cell carcinomas (SCCs) can be of therapeutic relevance. Here the authors show that loss of nuclear kinase ULK3 impairs the recruitment of two histone arginine methyltransferases, PRMT1 and PRMT5 to the promoter regions of genes of functions, hence, suppressing the tumorigenic potential of SCC cells.
- Sandro Goruppi
- , Andrea Clocchiatti
- & G. Paolo Dotto
-
Article
| Open AccessLY6D marks pre-existing resistant basosquamous tumor subpopulations
The identification of distinct cell populations with cellular plasticity in skin basal cell carcinoma is important for understanding treatment resistance mechanisms. Here, the authors identify the resistant LY6D+ basosquamous population that correlates with poor clinical outcomes.
- Daniel Haensel
- , Sadhana Gaddam
- & Anthony E. Oro
-
Article
| Open AccessA single-cell analysis reveals tumor heterogeneity and immune environment of acral melanoma
Studying the cell composition of acral melanoma at the single-cell level could provide some clues about its poor response to immunotherapy. Here, the authors analyse acral and cutaneous melanoma patient samples using single-cell RNA-sequencing, and reveal a severe immunosuppressive state in acral melanomas
- Chao Zhang
- , Hongru Shen
- & Jilong Yang
-
Article
| Open AccessBRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy
Targeted therapeutic options for NRAS-mutant melanoma are limited. Here, the authors show that under metabolic stress NRAS-mutant melanoma cells activate a BRAF-dependent glycolysis pathway for survival, leading to improve efficacy of sorafenib when combined with glycolysis inhibitors.
- Kimberley McGrail
- , Paula Granado-Martínez
- & Juan A. Recio
-
Article
| Open AccessCDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma
In patients with melanoma, increased RAS/mitogen-activated protein kinase (MAPK) pathway activity is known to drive chemotherapy resistance. Here, the authors identify CDK12 as a downstream effector of the RAS/MAPK pathway and therapeutic target which mediates chemotherapy resistance through increased expression of DNA repair associated genes.
- Thibault Houles
- , Geneviève Lavoie
- & Philippe P. Roux
-
Article
| Open AccessEvolution and modulation of antigen-specific T cell responses in melanoma patients
Previous studies have characterized the diversity and dynamics of the T cell receptor (TCR) repertoire in patients with solid cancer. Here, by analyzing TCR repertoire data from multiple datasets, the authors report that melanoma-associated antigen-specific TCRs can be used to separate metastatic melanoma patients from healthy controls and to follow anti-tumor responses in patients treated with immunotherapy.
- Jani Huuhtanen
- , Liang Chen
- & Satu Mustjoki
-
Article
| Open AccessMutated processes predict immune checkpoint inhibitor therapy benefit in metastatic melanoma
Tumour mutational burden is a biomarker of immune checkpoint inhibitor response, but their association is not fully understood. Here, the authors train classifiers to identify key mutated processes which show stable predictive performance in multiple melanoma cohorts.
- Andrew Patterson
- & Noam Auslander
-
Article
| Open AccessIn vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response
Standard assessment of immune infiltration of biopsies is not sufficient to accurately predict response to immunotherapy. Here, the authors show that reflectance confocal microscopy can be used to quantify dynamic vasculature and inflammatory features to better predict treatment response in skin cancers.
- Aditi Sahu
- , Kivanc Kose
- & Milind Rajadhyaksha