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Current treatment options for diabetic wounds face challenges due to low efficacy, as well as potential side effects and the necessity for repetitive treatments. To address these issues, we report a formulation utilizing trisulfide-derived lipid nanoparticle (TS LNP)-mRNA therapy to accelerate diabetic wound healing by repairing and reprogramming the microenvironment of the wounds. A library of reactive oxygen species (ROS)-responsive TS LNPs was designed and developed to encapsulate interleukin-4 (IL4) mRNA. TS2-IL4 LNP-mRNA effectively scavenges excess ROS at the wound site and induces the expression of IL4 in macrophages, promoting the polarization from the proinflammatory M1 to the anti-inflammatory M2 phenotype at the wound site. In a diabetic wound model of db/db mice, treatment with this formulation significantly accelerates wound healing by enhancing the formation of an intact epidermis, angiogenesis, and myofibroblasts. Overall, this TS LNP-mRNA platform not only provides a safe, effective, and convenient therapeutic strategy for diabetic wound healing but also holds great potential for clinical translation in both acute and chronic wound care. [ABSTRACT FROM AUTHOR]

The Human Cell Atlas (HCA) is a global partnership "to create comprehensive reference maps of all human cells-the fundamental units of life - as a basis for both understanding human health and diagnosing, monitoring, and treating disease." ( https://www.humancellatlas.org/ ) The atlas shall characterize cells from diverse individuals across the globe to better understand human biology. HCA proactively considers the priorities of, and benefits accrued to, contributing communities. Here, we lay out principles and action items that have been adopted to affirm HCA's commitment to equity so that the atlas is beneficial to all of humanity., Competing Interests: Competing interests: A.R. is an employee of Genentech, a member of the Roche group, and has equity in Roche. A.R. was a co-founder and equity holder of Celsius Therapeutics, is an equity holder in Immunitas, and until July 31, 2020 was an S.A.B. member of Thermo Fisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov. A.R. is an inventor on multiple patents related to single cell and spatial genomics. All other authors declare no competing interests., (© 2024. The Author(s).)

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving the understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA sequencing (scRNA-seq) to de novo identify 54 expression programs and construct a comprehensive cellular catalog of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Across cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, and cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A:HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases. Significance: This manuscript presents the first single-cell RNA sequencing atlas of PM tumor microenvironment. Findings of translational relevance, validated experimentally and using independent bulk cohorts, include identification of gene programs predictive of survival, a fetal-like endothelial cell population, and NKG2A blockade as a promising new immunotherapeutic intervention in PM., (©2024 American Association for Cancer Research.)

Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. In this study, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor-like cells in lung tumors. These cells are a major source of interleukin (IL)-1⍺, which drives the enhanced myeloid response. The age-associated decline of DNA methyltransferase 3A enhances IL-1⍺ production, and disrupting IL-1 receptor 1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.

As SARS-CoV-2 variants continue to emerge capable of evading neutralizing antibodies, it has become increasingly important to fully understand the breadth and functional profile of T cell responses to determine their impact on the immune surveillance of variant strains. Here, sampling healthy individuals, we profiled the kinetics and polyfunctionality of T cell immunity elicited by mRNA vaccination. Modeling of anti-spike T cell responses against ancestral and variant strains of SARS-CoV-2 suggested that epitope immunodominance and cross-reactivity are major predictive determinants of T cell immunity. To identify immunodominant epitopes across the viral proteome, we generated a comprehensive map of CD4 + and CD8 + T cell epitopes within non-spike proteins that induced polyfunctional T cell responses in convalescent patients. We found that immunodominant epitopes mainly resided within regions that were minimally disrupted by mutations in emerging variants. Conservation analysis across historical human coronaviruses combined with in silico alanine scanning mutagenesis of non-spike proteins underscored the functional importance of mutationally-constrained immunodominant regions. Collectively, these findings identify immunodominant T cell epitopes across the mutationally-constrained SARS-CoV-2 proteome, potentially providing immune surveillance against emerging variants, and inform the design of next-generation vaccines targeting antigens throughout SARS-CoV-2 proteome for broader and more durable protection., Competing Interests: Competing interests: CCB is a Bridge Fellow of the Parker Institute of Cancer Immunotherapy (PICI) and received research support. MB is a PICI Scholar. TO is an employee of Imprint Labs and a consultant for CDI Labs, Shennon Biotechnologies, and PopVax. BDG has received honoraria for speaking engagements from Merck, Bristol Meyers Squibb, and Chugai Pharmaceuticals; has received research funding from Bristol Meyers Squibb, Merck, and ROME Therapeutics; and has been a compensated consultant for Darwin Health, Merck, PMV Pharma, Shennon Biotechnologies, and Rome Therapeutics of which he is a co-founder. NB serves as an advisor/board member for Apricity, Break Bio, Carisma Therapeutics, CureVac, Genotwin, Novartis, Primevax, Rome Therapeutics, and Tempest Therapeutics; as a consultant for Genentech, Novartis, and ATP; receives research support from Dragonfly Therapeutics, Harbour Biomed Sciences, Regeneron Pharmaceuticals, and Ludwig Institute for Cancer Research; is an extramural member of PICI and receives research support. The remaining authors did not declare competing interests.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts., (© 2024 American Cancer Society.)

Monocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs' survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.