Aoyama K, Kawashima S, Saeki Y
… +13 more, Kawahara Y, Matsuzawa T, Saito N, Oikawa A, Morinaga T, Kawazu M, Togashi Y, Nakamura Y, Kawamura T, Kiniwa Y, Yamasaki O, Fukushima S, Inozume T
The most significant advantage of immune checkpoint inhibitors for patients with melanoma is their durable benefits. Particularly, most patients who achieve a complete response maintain a long-term relapse-free survival,...The most significant advantage of immune checkpoint inhibitors for patients with melanoma is their durable benefits. Particularly, most patients who achieve a complete response maintain a long-term relapse-free survival, even after the cessation of treatment. However, at present, more than half of patients cannot achieve such durable response. Therefore, it is necessary to elucidate mechanisms to achieve durable responses. The objectives of this study are to identify and characterize the molecules that mediate the durable antimelanoma T-cell response. We identified CD276 as a molecule that was downregulated in the regressing lesions of the durable responders. In vitro analysis revealed that exposure to IFN-γ released from activated T cells decreased CD276 expression in melanoma cells. In the autologous coculture assay, the abrogation of CD276 on melanoma cells significantly enhanced recognition and lysis by tumor-infiltrating lymphocytes. An immunohistochemistry analysis showed a tendency toward better progression-free survival after anti-PD-1 therapy in the group with low CD276 expression. We demonstrated that the inhibition of both PD-L1 and CD276 enhanced the antimelanoma response of in vitro tumor-infiltrating lymphocytes. In conclusion, inhibition of CD276 signaling has the potential to enhance the long-term therapeutic efficacy of immune checkpoint inhibitors.
Olivares-Guerrero M, González-Quesada A, Sahuquillo-Torralba A
… +34 more, Rivera-Díaz R, Carrascosa JM, Herrera-Acosta E, Belinchón I, Gómez-García FJ, Baniandrés O, Ruiz-Genao DP, López-Estebaranz JL, Rodríguez L, Cueva P, Ferrán M, Mateu A, Ruiz-Villaverde R, Riera-Monroig J, Ara-Martín M, Roncero-Riesco M, Gracia-Cazaña T, Abalde-Pintos MT, Pujol-Marco C, García-Donoso C, Del Alcázar E, Llamas-Velasco M, Suárez-Pérez JA, Rodríguez-Sánchez B, Díez-Madueño K, Ruiz-Carrascosa JC, Lezcano-Biosca V, Morales-Callaghan AM, Salgado-Boquete L, Montes-Torres A, González-Sixto B, Descalzo MÁ, García-Doval I, Daudén E
Infections are the most common adverse events associated with systemic treatment for psoriasis. Using data from the BIOBADADERM registry, we analyzed incidence rates of overall, serious, and special-interest infections a...Infections are the most common adverse events associated with systemic treatment for psoriasis. Using data from the BIOBADADERM registry, we analyzed incidence rates of overall, serious, and special-interest infections associated with biologics and oral small molecules. Adjusted incidence rate ratios were calculated using propensity score analysis, with adalimumab as the comparator. The study included 4820 patients (8826 treatment cycles; 20,829 patient years of follow-up). The overall incidence of serious infections was low across all treatments (5.33%), with infliximab showing the highest incidence rate. The most frequent serious infections were pneumonia, followed by COVID-19 pneumonia and cellulitis. Among nonserious infections, respiratory tract infections were most common, followed by COVID-19 and urinary tract infections. Risankizumab and ustekinumab were associated with significantly lower risk of overall infections than adalimumab (P < .002). The risk of Candida infections was significantly higher with bimekizumab, brodalumab, secukinumab, and ixekizumab. Guselkumab, secukinumab, ixekizumab, and ustekinumab were linked to reduced incidence of respiratory infections. Ixekizumab was associated with a lower risk of COVID-19 infection, whereas dimethyl fumarate showed an increased risk compared with adalimumab. Overall, our findings support the favorable safety profile of biologics and small molecules in psoriasis, particularly regarding serious infections.
Mycosis fungoides, a cutaneous T-cell lymphoma, is characterized by clonal proliferation of aberrant CD4 T cells and an evolving tumor microenvironment. Immunological heterogeneity across lesion stages and its role in di...Mycosis fungoides, a cutaneous T-cell lymphoma, is characterized by clonal proliferation of aberrant CD4 T cells and an evolving tumor microenvironment. Immunological heterogeneity across lesion stages and its role in disease severity remain poorly defined. We investigated lesion-specific aberrant T cells and immune cells in mycosis fungoides skin lesions using mass cytometry, cross-validated with public single-cell RNA-sequencing data, and assessed their associations with clinical outcome. Aberrant CD4CD7CD26CCR4 T cells expressing high levels of PD-1, PD-L1, and OX-40 were enriched in tumor lesions but absent in patches. Aberrant PD-L1 T cells exhibited central memory/effector memory phenotype, whereas aberrant PD-1 T cells demonstrated a terminal effector phenotype. Tumor microenvironment analysis revealed increased frequencies of PD-L1IgD memory B cells, PD-L1 regulatory T cells, PD-L1NCR type 3 innate lymphoid cells, and PD-1CD4/CD8 T cells in tumors. Patches lacked innate lymphoid cells, memory B cells and naïve/central memory CD8 T cells. Large cell transformation was associated with elevated frequencies of naïve B cells, PD-1 monocytes, and PD-1CD8 central memory/effector memory T cells. High frequencies of PD-L1 memory B cells, PD-1 dendritic cell, and PD-1 naïve CD4 T cells correlated with shorter progression-free survival, whereas normal levels of PD-1 transitional monocytes were associated with longer overall survival. Lesion-specific aberrant T cells and tumor microenvironment remodeling may drive mycosis fungoides severity and contribute to future immunotherapy.
Zhan Y, Dahabieh MS, Rajakumar A
… +9 more, Dobocan MC, M'Boutchou MN, Goncalves C, Lucy SL, Pettersson F, Topisirovic I, van Kempen L, Del Rincón SV, Miller WH
Jiang W, Xie X, Yang S
… +16 more, Xu R, Chang JW, Tang X, Yu R, Xie Y, Liu W, Tang R, Lun L, Buddenkotte J, Han J, Xu Y, Lu P, Ji S, Steinhoff M, Huang X, Wang F
Basophils are increasingly recognized as key contributors to the pathogenesis of atopic dermatitis (AD), yet how targeted therapies modulate their phenotype and function remains poorly defined. We investigated the effect...Basophils are increasingly recognized as key contributors to the pathogenesis of atopic dermatitis (AD), yet how targeted therapies modulate their phenotype and function remains poorly defined. We investigated the effects of dupilumab and abrocitinib on basophil activation in AD using flow cytometry, ex vivo stimulation assays, and immunofluorescence analysis. Compared with healthy controls, patients with AD showed elevated circulating basophil counts and increased expression of FcεRIα, MRGPRX2, and CD63. MRGPRX2-expressing basophils were also detected in lesional AD skin and exhibited further upregulation upon ex vivo stimulation. Both dupilumab and abrocitinib improved clinical symptoms, but their effects on basophils diverged. Dupilumab selectively reduced MRGPRX2 expression, whereas abrocitinib preferentially downregulated CD203c. Baseline CD63 expression on basophils correlated with clinical response to abrocitinib. Functional assays demonstrated that MRGPRX2 expression was significantly upregulated on basophils from patients with AD but not in healthy controls upon stimulation with N-formyl-Met-Leu-Phe or anti-IgE. Dupilumab selectively inhibited N-formyl-Met-Leu-Phe-induced MRGPRX2 upregulation without affecting IgE-mediated induction, whereas abrocitinib suppressed upregulation irrespective of the stimulus. These findings indicate that targeted therapies differentially modulate basophil hyperactivity, highlighting basophils as critical effector cells and MRGPRX2 as a promising biomarker for treatment response in AD.
Jia W, Katta N, Kennedy GT
… +13 more, Lee J, Nguyen E, Lai O, Jeong Y, Elsanadi R, Messele F, Johnson JE, Stemmer-Rachamimov AO, Nelson JS, Sierra R, Kelly KM, Durkin AJ, Milner TE
Cutaneous neurofibromas (cNFs) occur in individuals with germline neurofibromatosis type I pathogenic variants. Current management involves monitoring and limited surgical removal. Nascent cNFs are lesions detectable onl...Cutaneous neurofibromas (cNFs) occur in individuals with germline neurofibromatosis type I pathogenic variants. Current management involves monitoring and limited surgical removal. Nascent cNFs are lesions detectable only through advanced imaging and not observable with the unaided eye. Noninvasive early detection may enable intervention before cNF become visible. We introduce an imaging approach integrating spatial frequency domain imaging and high-frequency ultrasound to identify and characterize suspected nascent cNFs. In 21 participants with neurofibromatosis type I, we identified 152 suspected nascent lesions using spatial frequency domain imaging as skin regions with decreased optical scattering at near-infrared wavelengths. Of these, 120 were imaged with high-frequency ultrasound, and 93% demonstrated subsurface hypoechoic dermal structures. Paired analyses of the reduced scattering coefficient (μ') at 851 nm showed that μ' within suspected nascent cNFs was significantly lower than that of adjacent uninvolved skin, supporting μ' as a candidate imaging feature for nascent cNFs. Statistical variation in overlying dermal thickness and lesion dimensions is summarized. Integrating spatial frequency domain imaging and high-frequency ultrasound represents a multimodal approach for imaging characterization of suspected nascent cNFs and may advance the understanding of cNF progression and the development of treatment strategies. This feasibility study does not establish nascent cNF diagnostic detection accuracy because histologic confirmation was limited.
Epithelial basal cells exhibit heterogeneity, with populations occupying specific tissue regions. Human skin displays an undulating (rete ridge) structure at the epidermal-dermal junction that supports the mechanical int...Epithelial basal cells exhibit heterogeneity, with populations occupying specific tissue regions. Human skin displays an undulating (rete ridge) structure at the epidermal-dermal junction that supports the mechanical integrity of tissue. By contrast, murine dorsal skin lacks such pronounced undulations, limiting analyses of how tissue architecture affects the localization and behavior of distinct epithelial populations. In this study, murine oral mucosa, which possesses an undulating structure, is used to characterize the spatial organization of epithelial heterogeneity in vivo. H2B-GFP label-retaining cells (LRCs) and non-LRCs exhibit spatially biased distributions along the undulating structure, with LRC and non-LRC populations enriched in the inter-ridge and rete ridge regions, respectively. Lineage tracing with Dlx1- and Slc1a3-CreER shows that labeled cells preferentially localize to the inter-ridge and rete ridge, respectively, and that their lineage contribution to epithelial maintenance is regionally biased. RNA sequencing of the LRC and non-LRC fractions suggests their transcriptional differences and identifies Il1r2 and Slc1a3 as genes enriched in these epithelial populations. A 3-dimensional culture using micropatterned collagen scaffolds that reproduce undulating structures partially induces a spatial bias in epithelial cell proliferation. Thus, this study proposes the undulating structure as a topographical microenvironment that contributes to the spatial organization of epithelial heterogeneity in stratified epithelia.
Atopic dermatitis is a prevalent chronic inflammatory skin condition affecting up to 20% of children and 10% of adults in Africa. The management of atopic dermatitis relies heavily on the use of emollients, which form th...Atopic dermatitis is a prevalent chronic inflammatory skin condition affecting up to 20% of children and 10% of adults in Africa. The management of atopic dermatitis relies heavily on the use of emollients, which form the foundation of treatment by enhancing the skin barrier and preventing the condition's flare-ups. However, access to emollients remains a significant challenge across Africa, impeding effective treatment and worsening the QOL in those affected. This research utilized a cross-sectional survey conducted between October 2023 and April 2024, gathering data from dermatologists in 16 African countries. Information was collected regarding the availability of traditional and industrial emollients, costs, economic conditions, and healthcare infrastructure. Results indicate that traditional emollients such as coconut oil and shea butter are widely available, although their quality and consistency vary. Imported emollients, including Vaseline petroleum jelly and products from brands such as Dexeryl, Topicrem, and CeraVe, are more commonly prescribed. However, the cost of these imported products is a significant barrier. In conclusion, this study highlights significant disparities and major economic barriers to accessing emollient treatments for atopic dermatitis in Sub-Saharan Africa.
Keloids are a chronic, refractory, wound-triggered fibroproliferative disorder characterized by fibroblast overproduction, excessive extracellular matrix deposition, persistent inflammation, and invasive growth beyond or...Keloids are a chronic, refractory, wound-triggered fibroproliferative disorder characterized by fibroblast overproduction, excessive extracellular matrix deposition, persistent inflammation, and invasive growth beyond original wound boundaries. Although keloid risk is associated with numerous genetic loci and skin of color, keloid pathogenesis remains incompletely understood. Multiomic technologies have identified cell populations and signaling networks associated with keloid pathogenesis. Emerging evidence highlights adipocyte lipolysis, epigenetic regulation by microRNAs, and disrupted vitamin D signaling as modulators of tissue repair and fibrosis. Genetic studies further implicate heritable risk factors. Integration of these approaches offers insights and therapeutic opportunities for this prevalent, debilitating condition.
Inherited genetic susceptibility to cutaneous melanoma ranges from common low-risk variants to rare high-penetrance variants. Although highly penetrant variants in genes such as CDKN2A explain many cases with multiple pr...Inherited genetic susceptibility to cutaneous melanoma ranges from common low-risk variants to rare high-penetrance variants. Although highly penetrant variants in genes such as CDKN2A explain many cases with multiple primary melanomas, a substantial proportion of patients are negative for known high-penetrance drivers. We studied 79 patients with 5 or more melanomas who tested negative for pathogenic variants in established high-penetrance melanoma genes, using whole-exome sequencing to identify rare coding variants and combining this with SNP array data to calculate polygenic risk scores for each individual. Although variants of uncertain or moderate effect were identified in genes involved in pigmentation and DNA damage response, no single variant explained the multiple primary melanoma phenotype in most cases. In contrast, MC1R risk alleles were significantly enriched, and polygenic risk score was markedly higher in this cohort than in population-based melanoma cases. Individuals carrying rare potentially pathogenic variants in cancer genes tended to have lower polygenic risk scores, suggesting complementary genetic architectures. These findings indicate that, in the absence of high-penetrance variants, the risk for multiple primary melanoma is largely driven by the cumulative burden of low- and moderate-risk alleles, supporting the integration of polygenic risk scores and rare variant data for melanoma risk stratification.