N6-methyladenosine RNA Methylation Correlates with Immune Microenvironment and Immunotherapy Response of Melanoma.

RNA methylation normally inhibits the self-recognition and immunogenicity of RNA. As such, it is likely an important inhibitor of cancer immune recognition in the tumor microenvironment, but how N6-methyladenosine (m6A) affects prognosis and treatment response remains unknown. In eight independent melanoma cohorts (1,564 patients), the modification patterns of 21 m6A gene signatures were systematically correlated with the immune cell infiltration of melanoma tumor microenvironment. m6A modification patterns for each patient were quantified using the principal component analysis method, yielding an m6Ascore that reflects the abundance of m6A RNA modifications. Two different m6A modification patterns were observed in patients with melanoma, separated into high and low m6Ascores that correlated with survival and treatment response. Low m6Ascores were characterized by an immune-inflamed phenotype, with 61.1% 5-year survival. High m6Ascores were characterized by an immune-excluded phenotype, with 52.2% 5-year survival. Importantly, lower m6Ascores correlated with more sensitive anti-PD-1 and anti-CTLA4 treatment responses, with 90% of patients with low m6Ascore responding, whereas 10% of those with high m6Ascore nonresponding (in cohort GSE63557). At single-cell and spatial transcriptome resolution, m6Ascore reflects melanoma malignant progression, immune exhaustion, and resistance to immune checkpoint blockade therapy. Hence, the m6Ascore correlates to an important facet of tumor immune escape as a tool for personalized medicine to guide immunotherapy in patients with melanoma.

Commensal microbiome promotes hair follicle regeneration by inducing keratinocyte HIF-1α signaling and glutamine metabolism.

Tissue injury induces metabolic changes in stem cells, which likely modulate regeneration. Using a model of organ regeneration called wound-induced hair follicle neogenesis (WIHN), we identified skin-resident bacteria as key modulators of keratinocyte metabolism, demonstrating a positive correlation between bacterial load, glutamine metabolism, and regeneration. Specifically, through comprehensive multiomic analysis and single-cell RNA sequencing in murine skin, we show that bacterially induced hypoxia drives increased glutamine metabolism in keratinocytes with attendant enhancement of skin and hair follicle regeneration. In human skin wounds, topical broad-spectrum antibiotics inhibit glutamine production and are partially responsible for reduced healing. These findings reveal a conserved and coherent physiologic context in which bacterially induced metabolic changes improve the tolerance of stem cells to damage and enhance regenerative capacity. This unexpected proregenerative modulation of metabolism by the skin microbiome in both mice and humans suggests important methods for enhancing regeneration after injury.

Neutrophil extracellular traps impair regeneration.

Fibrosis is a major health burden across diseases and organs. To remedy this, we study wound-induced hair follicle neogenesis (WIHN) as a model of non-fibrotic healing that recapitulates embryogenesis for de novo hair follicle morphogenesis after wounding. We previously demonstrated that TLR3 promotes WIHN through binding wound-associated dsRNA, the source of which is still unclear. Here, we find that multiple distinct contexts of high WIHN all show a strong neutrophil signature. Given the correlation between neutrophil infiltration and endogenous dsRNA release, we hypothesized that neutrophil extracellular traps (NETs) likely release nuclear spliceosomal U1 dsRNA and modulate WIHN. However, rather than enhance regeneration, we find mature neutrophils inhibit WIHN such that mice with mature neutrophil depletion exhibit higher WIHN. Similarly, Pad4 null mice, which are defective in NET production, show augmented WIHN. Finally, using single-cell RNA sequencing, we identify a dramatic increase in mature and activated neutrophils in the wound beds of low regenerating Tlr3-/- mice. Taken together, these results demonstrate that although mature neutrophils are stimulated by a common pro-regenerative cue, their presence and NETs hinder regeneration.

Radiation recall dermatitis following letrozole administration in patient with a remote history of radiation therapy.

We report the case of letrozole-induced radiation recall dermatitis (RRD) in a patient with a remote history of radiation therapy. There is only one previously known case of RRD triggered by letrozole in a patient with a recent (<3 month) history of radiation. Previously, only four other cases of aromatase-inhibitor-induced RRD have been reported. This case is significant for cancer care teams considering personalized treatments. In addition, improved long-term outcomes in cancer patients may lead to increases in and underdiagnoses of RRD. Likewise, RRD is patient specific, exacerbating health concerns, and can be difficult to recognize without proper awareness, documentation, and classification of triggering drugs. The authors hope to address these issues in this report.

Bacteria induce skin regeneration via IL-1ß signaling.

Environmental factors that enhance regeneration are largely unknown. The immune system and microbiome are attributed roles in repairing and regenerating structure but their precise interplay is unclear. Here, we assessed the function of skin bacteria in wound healing and wound-induced hair follicle neogenesis (WIHN), a rare adult organogenesis model. WIHN levels and stem cell markers correlate with bacterial counts, being lowest in germ-free (GF), intermediate in conventional specific pathogen-free (SPF), and highest in wild-type mice, even those infected with pathogenic Staphylococcus aureus. Reducing skin microbiota via cage changes or topical antibiotics decreased WIHN. Inflammatory cytokine IL-1ß and keratinocyte-dependent IL-1R-MyD88 signaling are necessary and sufficient for bacteria to promote regeneration. Finally, in a small trial, a topical broad-spectrum antibiotic also slowed skin wound healing in adult volunteers. These results demonstrate a role for IL-1ß to control morphogenesis and support the need to reconsider routine applications of topical prophylactic antibiotics.

Association of the Psoriatic Microenvironment With Treatment Response.

Importance: The ability to predict the efficacy of systemic psoriasis therapy based on immune profiles in skin biopsies could reduce the use of inappropriate treatment and its associated costs and adverse events. It could considerably decrease drug development trial costs as well. Objective: To develop a bioinformatic gene signature score derived from skin mRNA to predict psoriasis treatment outcomes for a variety of therapies. Design, Setting, and Participants: In this decision analytical model using 1145 skin samples from different cohorts of 12 retrospective psoriasis studies, samples were analyzed using the CIBERSORT algorithm to define the immune landscape of psoriasis lesions and controls. Random forest classification and principal component analysis algorithms were used to estimate psoriatic microenvironment (PME) signature genes and construct a PME score. Overall, 85 and 421 psoriasis lesions from 1 and 4 independent cohorts were used as discovery and validation studies, respectively. Among them, 157, 71, 89, and 90 psoriasis lesions were treated with etanercept, tofacitinib, adalimumab, and methotrexate, respectively. Main Outcomes and Measures: Number of weeks after treatment initiation when responders and nonresponders could be predicted. Results: Overall, 22 immune cell subtypes formed infiltration patterns that differentiated psoriasis lesions from healthy skin. In psoriasis lesions, the expression of 33 PME signature genes defined 2 immune phenotypes and in aggregate could be simplified to a numerical PME score. A high PME score, characterized by keratinocyte differentiation, correlated with a better treatment response (Psoriasis Area and Severity Index [PASI] reduction, 75.8%; 95% CI, 69.4% to 82.2%; P = .03), whereas a low PME score exhibited an immune activation signature and was associated with a worse response (PASI reduction, 53.5%; 95% CI, 45.3% to 61.7%; P = .03). The PME score at week 4 after treatment initiation correlated with future responder vs nonresponder to treatment status 8 to 12 weeks earlier than PASI reduction for etanercept, methotrexate plus adalimumab, and tofacitinib. Conclusions and Relevance: The PME score is a biometric score that may predict clinical efficacy of systemic psoriasis therapy in advance of clinical responses. As an application of personalized medicine, it may reduce the exposure of patients with psoriasis to ineffective and expensive therapies.