Changes in Merkel cell oncoprotein antibodies after radiation therapy in curatively treated Merkel cell carcinoma and association with recurrence.

Background: Serum antibodies to the Merkel oncoprotein (AMERK) are detectable in approximately 50% of patients with Merkel cell carcinoma (MCC) and can be used to monitor for recurrence. The objective of this study was to characterize AMERK levels in patients receiving curative-intent radiation therapy (RT) for MCC and identify associations between AMERK and recurrence.

Methods: This was a retrospective study of patients with MCC who had baseline AMERK measurements before they received curative-intent RT from 2010 to 2020.

Slide-tags enables single-nucleus barcoding for multimodal spatial genomics.

Recent technological innovations have enabled the high-throughput quantification of gene expression and epigenetic regulation within individual cells, transforming our understanding of how complex tissues are constructed. However, missing from these measurements is the ability to routinely and easily spatially localize these profiled cells. We developed a strategy, Slide-tags, in which single nuclei within an intact tissue section are tagged with spatial barcode oligonucleotides derived from DNA-barcoded beads with known positions.

Slide-tags: scalable, single-nucleus barcoding for multi-modal spatial genomics.

Recent technological innovations have enabled the high-throughput quantification of gene expression and epigenetic regulation within individual cells, transforming our understanding of how complex tissues are constructed. Missing from these measurements, however, is the ability to routinely and easily spatially localise these profiled cells. We developed a strategy, Slide-tags, in which single nuclei within an intact tissue section are 'tagged' with spatial barcode oligonucleotides derived from DNA-barcoded beads with known positions.

Spatial maps of T cell receptors and transcriptomes reveal distinct immune niches and interactions in the adaptive immune response.

T cells mediate antigen-specific immune responses to disease through the specificity and diversity of their clonotypic T cell receptors (TCRs). Determining the spatial distributions of T cell clonotypes in tissues is essential to understanding T cell behavior, but spatial sequencing methods remain unable to profile the TCR repertoire. Here, we developed Slide-TCR-seq, a 10-μm-resolution method, to sequence whole transcriptomes and TCRs within intact tissues.

Melanoma arising in extracutaneous cellular blue naevus: report of two cases with comparison to cutaneous counterparts and uveal melanoma.

Aims: Blue naevi are benign melanocytic lesions that typically occur in the dermis. Melanoma arising in blue naevus is rare, and shows a molecular profile distinct from conventional forms of cutaneous melanoma and more similar to uveal melanoma and central nervous system (CNS) melanocytomas. In contrast to conventional cutaneous melanoma, these tumour types typically show activating driver mutations in GNAQ or GNA11, a low mutational burden without evidence of a UV signature and a reproducible pattern of chromosomal copy number changes.

Characterization of clinical outcomes after shorter course hypofractionated and standard-course radiotherapy for stage I-III curatively-treated Merkel cell carcinoma.

Background: Limited data exists regarding the efficacy of curative hypofractionated radiotherapy (hypo-RT) regimens compared to conventionally-fractionated radiotherapy (conv-RT) for Merkel cell carcinoma (MCC).

Methods: A retrospective analysis of 241 patients diagnosed with non-metastatic MCC from 2005-2021 and who received RT at Dana-Farber/Brigham & Women's Cancer Center. The primary outcome was cumulative incidence of in-field locoregional relapse using Gray's test with competing risks of death and isolated out-of-field recurrence.

An activation to memory differentiation trajectory of tumor-infiltrating lymphocytes informs metastatic melanoma outcomes.

There is a need for better classification and understanding of tumor-infiltrating lymphocytes (TILs). Here, we applied advanced functional genomics to interrogate 9,000 human tumors and multiple single-cell sequencing sets using benchmarked T cell states, comprehensive T cell differentiation trajectories, human and mouse vaccine responses, and other human TILs. Compared with other T cell states, enrichment of T memory/resident memory programs was observed across solid tumors.

Landscape of helper and regulatory antitumour CD4 T cells in melanoma.

Within the tumour microenvironment, CD4 T cells can promote or suppress antitumour responses through the recognition of antigens presented by human leukocyte antigen (HLA) class II molecules, but how cancers co-opt these physiologic processes to achieve immune evasion remains incompletely understood. Here we performed in-depth analysis of the phenotype and tumour specificity of CD4 T cells infiltrating human melanoma specimens, finding that exhausted cytotoxic CD4 T cells could be directly induced by melanoma cells through recognition of HLA class II-restricted neoantigens, and also HLA class I-restricted tumour-associated antigens. CD4 T regulatory (T) cells could be indirectly elicited through presentation of tumour antigens via antigen-presenting cells.

Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma.

Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient ( NCT01970358 ). All patients were alive and six were without evidence of active disease.

ATF-3 expression inhibits melanoma growth by downregulating ERK and AKT pathways.

Activating transcription factor 3 (ATF-3), a cyclic AMP-dependent transcription factor, has been shown to play a regulatory role in melanoma, although its function during tumor progression remains unclear. Here, we demonstrate that ATF-3 exhibits tumor suppressive function in melanoma. Specifically, ATF-3 nuclear expression was significantly diminished with melanoma progression from nevi to primary to metastatic patient melanomas, correlating low expression with poor prognosis.

Author Correction: A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors.

Single-cell genomics is essential to chart tumor ecosystems. Although single-cell RNA-Seq (scRNA-Seq) profiles RNA from cells dissociated from fresh tumors, single-nucleus RNA-Seq (snRNA-Seq) is needed to profile frozen or hard-to-dissociate tumors. Each requires customization to different tissue and tumor types, posing a barrier to adoption.

Inactivation of Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade.

The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti-PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene , whereas a sensitive tumor from the same patient did not.

Inhibition of MICA and MICB Shedding Elicits NK-Cell-Mediated Immunity against Tumors Resistant to Cytotoxic T Cells.

Resistance to cytotoxic T cells is frequently mediated by loss of MHC class I expression or IFNγ signaling in tumor cells, such as mutations of or genes. Natural killer (NK) cells could potentially target such resistant tumors, but suitable NK-cell-based strategies remain to be developed. We hypothesized that such tumors could be targeted by NK cells if sufficient activating signals were provided.

KEYNOTE-716: Phase III study of adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma.

Patients with high-risk stage II melanoma are at significant risk for recurrence after surgical resection. Adjuvant treatment options to lower the risk for distant metastases are limited. Although adjuvant IFN-α2b is associated with improved relapse-free survival in patients with high-risk melanoma, toxicity and limited overall survival benefits limit its use.

Discovery of specialized NK cell populations infiltrating human melanoma metastases.

NK cells contribute to protective antitumor immunity, but little is known about the functional states of NK cells in human solid tumors. To address this issue, we performed single-cell RNA-seq analysis of NK cells isolated from human melanoma metastases, including lesions from patients who had progressed following checkpoint blockade. This analysis identified major differences in the transcriptional programs of tumor-infiltrating compared with circulating NK cells.

Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies.

Most targeted cancer therapies fail to achieve complete tumor regressions or attain durable remissions. To understand why these treatments fail to induce robust cytotoxic responses despite appropriately targeting oncogenic drivers, here we systematically interrogated the dependence of cancer cells on the BCL-2 family of apoptotic proteins after drug treatment. We observe that multiple targeted therapies, including BRAF or EGFR inhibitors, rapidly deplete the pro-apoptotic factor NOXA, thus creating a dependence on the anti-apoptotic protein MCL-1.

Utility of Level III Axillary Node Dissection in Melanoma Patients with Palpable Axillary Lymph Node Disease.

Background: The Multicenter Selective Lymphadenectomy Trial II results suggest that future radical axillary lymphadenectomy (ALND) will be performed for bulkier metastatic disease. The utility of level III lymph node (LN) dissection in melanoma patients with palpable metastatic axillary disease was assessed.

Methods: We performed a retrospective chart review of patients who underwent ALND (levels I-III) for metastatic melanoma from 2005 to 2017.

Corrigendum: An immunogenic personal neoantigen vaccine for patients with melanoma.

This corrects the article DOI: 10.1038/nature22991.