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Intrahepatic cholangiocarcinoma (iCCA) has poor prognosis and elucidation of the molecular mechanisms underlying iCCA malignancy is of great significance. Glycosylation, an important post-translational modification, is closely associated with tumor progression. Altered glycosylation, including aberrant sialylation resulting from abnormal expression of sialyltransferases (STs) and neuraminidases (NEUs), is a significant feature of cancer cells. However, there is limited information on the roles of STs and NEUs in iCCA malignancy. Here, utilizing our proteogenomic resources from a cohort of 262 iCCA patients, we identified ST3GAL1 as a prognostically relevant molecule in iCCA. Moreover, overexpression of ST3GAL1 promoted proliferation, migration and invasion and inhibited apoptosis of iCCA cells in vitro. Through proteomic analyses, we identified the downstream pathway potentially regulated by ST3GAL1, which was the NF-κB signaling pathway and further demonstrated that this pathway was positively correlated with malignancy in iCCA cells. Notably, glycoproteomics showed that O-glycosylation was changed in iCCA cells with high ST3GAL1 expression. Importantly, the altered O-glycopeptides underscored the potential utility of O-glycosylation profiling as a discriminatory marker for iCCA cells with ST3GAL1 overexpression. Additionally, miR-320b was identified as a post-transcriptional regulator of ST3GAL1, capable of suppressing ST3GAL1 expression and then reducing the proliferation, migration and invasion abilities of iCCA cell lines. Taken together, these results suggest ST3GAL1 could serve as a promising therapeutic target for iCCA.
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BACKGROUND: Gallbladder cancer (GBC) is the most common and lethal malignancy of the biliary tract that lacks effective therapy. In many GBC cases, infiltration into adjacent organs or distant metastasis happened long before the diagnosis, especially the direct liver invasion, which is the most common and unfavorable way of spreading. METHODS: Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), proteomics, and multiplexed immunohistochemistry (mIHC) were performed on GBC across multiple tumor stages to characterize the tumor microenvironment (TME), focusing specifically on the preferential enrichment of neutrophils in GBC liver invasion (GBC-LI). RESULTS: Multi-model Analysis reveals the immunosuppressive TME of GBC-LI that was characterized by the enrichment of neutrophils at the invasive front. We identified the context-dependent transcriptional states of neutrophils, with the Tumor-Modifying state being associated with oxidized low-density lipoprotein (oxLDL) metabolism. In vitro assays showed that the direct cell-cell contact between GBC cells and neutrophils led to the drastic increase in oxLDL uptake of neutrophils, which was primarily mediated by the elevated OLR1 on neutrophils. The oxLDL-absorbing neutrophils displayed a higher potential to promote tumor invasion while demonstrating lower cancer cytotoxicity. Finally, we identified a neutrophil-promoting niche at the invasive front of GBC-LI that constituted of KRT17+ GBC cells, neutrophils, and surrounding fibroblasts, which may help cultivate the oxLDL-absorbing neutrophils. CONCLUSIONS: Our study reveals the existence of a subset of pro-tumoral neutrophils with a unique ability to absorb oxLDL via OLR1, a phenomenon induced through cell-cell contact with KRT17+ GBC cells in GBC-LI.
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B lymphocytes are essential mediators of humoral immunity and play multiple roles in human cancer. To decode the functions of tumor-infiltrating B cells, we generated a B cell blueprint encompassing single-cell transcriptome, B cell-receptor repertoire, and chromatin accessibility data across 20 different cancer types (477 samples, 269 patients). B cells harbored extraordinary heterogeneity and comprised 15 subsets, which could be grouped into two independent developmental paths (extrafollicular versus germinal center). Tumor types grouped into the extrafollicular pathway were linked with worse clinical outcomes and resistance to immunotherapy. The dysfunctional extrafollicular program was associated with glutamine-derived metabolites through epigenetic-metabolic cross-talk, which promoted a T cell-driven immunosuppressive program. These data suggest an intratumor B cell balance between extrafollicular and germinal-center responses and suggest that humoral immunity could possibly be harnessed for B cell-targeting immunotherapy.
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Linfocitos B , Centro Germinal , Linfocitos Infiltrantes de Tumor , Neoplasias , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/genética , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos B/inmunología , Centro Germinal/inmunología , Inmunoterapia , Transcriptoma , Análisis de la Célula Individual , Epigénesis Genética , Inmunidad Humoral , Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores de Antígenos de Linfocitos B/inmunologíaRESUMEN
SUMMARY: Nutrients are essential for supporting tumor growth and immune cell function in the tumor microenvironment, but emerging evidence reveals a paradoxical competition and collaboration between the metabolic demands of proliferating cancer cells and immune cell activation. Dietary interventions and metabolic immunoengineering offer promise to selectively modulate cancer and immune cell metabolism by targeting metabolic sensing processes rather than pathways directly, moving beyond conventional ideas and heralding an exciting new era of immunometabolism discovery and translation.
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Neoplasias , Humanos , Neoplasias/metabolismo , Microambiente TumoralRESUMEN
Neutrophils, the most abundant and efficient defenders against pathogens, exert opposing functions across cancer types. However, given their short half-life, it remains challenging to explore how neutrophils adopt specific fates in cancer. Here, we generated and integrated single-cell neutrophil transcriptomes from 17 cancer types (225 samples from 143 patients). Neutrophils exhibited extraordinary complexity, with 10 distinct states including inflammation, angiogenesis, and antigen presentation. Notably, the antigen-presenting program was associated with favorable survival in most cancers and could be evoked by leucine metabolism and subsequent histone H3K27ac modification. These neutrophils could further invoke both (neo)antigen-specific and antigen-independent T cell responses. Neutrophil delivery or a leucine diet fine-tuned the immune balance to enhance anti-PD-1 therapy in various murine cancer models. In summary, these data not only indicate the neutrophil divergence across cancers but also suggest therapeutic opportunities such as antigen-presenting neutrophil delivery.
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Presentación de Antígeno , Neoplasias , Neutrófilos , Animales , Humanos , Ratones , Antígenos de Neoplasias , Leucina/metabolismo , Neoplasias/inmunología , Neoplasias/patología , Neutrófilos/metabolismo , Linfocitos T , Análisis de Expresión Génica de una Sola CélulaRESUMEN
KRAS mutations are causally linked to protumor inflammation and are identified as driving factors in tumorigenesis. Here, using multiomics data gathered from a large set of patients, we showed that KRAS mutation was associated with a specific landscape of alternative mRNA splicing that connected to myeloid inflammation in intrahepatic cholangiocarcinoma (iCCA). Then, we identified a negative feedback mechanism in which the upregulation of interleukin 1 receptor antagonist (IL1RN)-201/203 due to alternative splicing confers vital anti-inflammatory effects in KRAS-mutant iCCA. In KRAS-mutant iCCA mice, both IL1RN-201/203 upregulation and anakinra treatment ignited a significant antitumor immune response by altering neutrophil recruitment and phenotypes. Furthermore, anakinra treatment synergistically enhanced anti-PD-1 therapy to activate intratumoral GZMB+ CD8+ T cells in KRAS-mutant iCCA mice. Clinically, we found that high IL1RN-201/203 levels in patients with KRAS-mutant iCCA were significantly associated with superior response to anti-PD-1 immunotherapy. SIGNIFICANCE: This work describes a novel inflammatory checkpoint mediated by IL1RN alternative splicing variants that may serve as a promising basis to develop therapeutic options for KRAS-mutant iCCA and other cancers. This article is featured in Selected Articles from This Issue, p. 2109.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Animales , Ratones , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Conductos Biliares Intrahepáticos/patología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Inflamación/tratamiento farmacológico , Inflamación/genéticaRESUMEN
Organoid models have the potential to recapitulate the biological and pharmacotypic features of parental tumors. Nevertheless, integrative pharmaco-proteogenomics analysis for drug response features and biomarker investigation for precision therapy of patients with liver cancer are still lacking. We established a patient-derived liver cancer organoid biobank (LICOB) that comprehensively represents the histological and molecular characteristics of various liver cancer types as determined by multiomics profiling, including genomic, epigenomic, transcriptomic, and proteomic analysis. Proteogenomic profiling of LICOB identified proliferative and metabolic organoid subtypes linked to patient prognosis. High-throughput drug screening revealed distinct response patterns of each subtype that were associated with specific multiomics signatures. Through integrative analyses of LICOB pharmaco-proteogenomics data, we identified the molecular features associated with drug responses and predicted potential drug combinations for personalized patient treatment. The synergistic inhibition effect of mTOR inhibitor temsirolimus and the multitargeted tyrosine kinase inhibitor lenvatinib was validated in organoids and patient-derived xenografts models. We also provide a user-friendly web portal to help serve the biomedical research community. Our study is a rich resource for investigation of liver cancer biology and pharmacological dependencies and may help enable functional precision medicine.
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Neoplasias Hepáticas , Proteogenómica , Humanos , Proteómica , Medicina de Precisión , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , OrganoidesRESUMEN
BACKGROUND: Immunotherapy has resulted in impressive objective response rates and durable tumour remission, but only in a subset of gastric cancer (GC) patients. The PD-L1 combined positive score is the most widely used tissue-based biomarker for anti-PD-1/PD-L1 therapy; however, this unidimensional method has limitations. Next-generation exploration of tissue-based biomarkers for GC requires characterisation of various cellular markers and key immunoregulatory molecule expression in situ. Thus, a complete, stepwise solution covering the entire process from staining samples to cross-site utilisation of pathomics data is urgently needed. METHODS: With the advanced multispectral imaging analysis method, web-based data repository, and interactive sharing technology, we conducted a project entitled Gastric Cancer Multiplex Immunohistochemistry Atlas from Peking University Cancer Hospital (GMAP). We propose a standard pipeline covering sample collection, staining, scanning multispectral images, constructing a spectral library, identifying and phenotyping cells, positioning each element, and quantitatively extracting immune features. We designed an open-access relational database to explore tissue-based biomarkers to determine PD-1/PD-L1 blockade efficacy. RESULTS: The GMAP project detected the functional status and spatial location of more than 50 million cells using 15 markers in 80 GC patients, based on which billions of cell pairs were recognised, highlighting the rich spatial arrangement information and the fine tumour microenvironment structure. We generated a tumour-immune atlas using the count and spatial features of 65 immune cell types. We eventually selected the indicators and built a comprehensive risk-scoring system. Patients with higher risk score showed superior immunotherapy-related progression-free survival (irPFS) (hazard ratio [HR]: 3.19; P < 0.001; median irPFS: 4.87 versus 19.87months, respectively) and immunotherapy-related overall survival (HR: 3.10; P = 0.001; median irPFS: 10.03 versus 24.87months, respectively) compared with lower risk patients, demonstrating their potential for guiding anti-PD-1/PD-L1-based immunotherapy. Importantly, an easy-to-use and versatile web server was built to promote tissue-based biomarker exploration in GC. CONCLUSION: The GMAP project highlighted the clinical value of tissue-based immune features as biomarkers for immunotherapeutic decision-making. We present a well-designed, detailed workflow for the orderly generation and use of a high-quality, spatially resolved pathological database.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1/metabolismo , Inmunohistoquímica , Instituciones Oncológicas , Universidades , Biomarcadores de Tumor/metabolismo , Inmunoterapia/métodos , Microambiente TumoralRESUMEN
Enhanced glycolysis and accumulation of lactate is a common feature in various types of cancer. Intracellular lactate drives a recently described type of posttranslational modification, lysine lactylation (Kla), on core histones. However, the impact of lactylation on biological processes of tumour cells remains largely unknown. Here we show a global lactylome profiling on a prospectively collected hepatitis B virus-related hepatocellular carcinoma (HCC) cohort. Integrative lactylome and proteome analysis of the tumours and adjacent livers identifies 9,275 Kla sites, with 9,256 sites on non-histone proteins, indicating that Kla is a prevalent modification beyond histone proteins and transcriptional regulation. Notably, Kla preferentially affects enzymes involved in metabolic pathways, including the tricarboxylic acid cycle, and carbohydrate, amino acid, fatty acid and nucleotide metabolism. We further verify that lactylation at K28 inhibits the function of adenylate kinase 2, facilitating the proliferation and metastasis of HCC cells. Our study therefore reveals that Kla plays an important role in regulating cellular metabolism and may contribute to HCC progression.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Histonas/metabolismo , LactatosRESUMEN
BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is the second-most lethal primary liver cancer and its prognosis remains dismal. N-glycosylation, which is biosynthesized by a number of glycosyltransferases, plays an important role in a variety of biological processes and is associated with cancer development and progression. METHODS: Based on our previous proteogenomic resources from an iCCA cohort of 262 patients, fucosyltransferases 8 (FUT8) showed significant prognosis relevance in iCCA. Tumor tissues from iCCA patients were used to evaluate the correlation between its expression and clinical information. Gain/loss-of-function experiments in iCCA cell lines were performed to elucidate the biological function of FUT8. In addition, its downstream pathways and post-transcriptional regulators were inferred and verified. RESULTS: Elevated FUT8 expression was clinically associated with worse overall survival in iCCA patients. Its overexpression promoted migration, invasion and proliferation ability of iCCA cells. In addition, miR-122-5p was found to act as a post-transcriptional regulator of FUT8 and proved to inhibit FUT8 expression and then suppress the proliferation and migration ability of iCCA cell lines. Furthermore, FUT8 was observed to promote iCCA development through PI3K/AKT signaling pathway. CONCLUSIONS: These findings demonstrated that FUT8, regulated by miR-122-5p, could be a tumor promoter of iCCA through PI3K/AKT signaling pathway.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , MicroARNs , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Colangiocarcinoma/patología , Conductos Biliares Intrahepáticos/metabolismo , MicroARNs/metabolismo , Proliferación Celular , Línea Celular TumoralRESUMEN
The molecular landscape and pathogenesis of focal nodular hyperplasia (FNH) have yet to be elucidated. We performed multi-omics approaches on FNH and paired normal liver tissues from 22 patients, followed by multi-level bioinformatic analyses and experimental validations. Generally, FNH had low mutation burden with low variant allele frequencies, and the mutation frequency significantly correlated with proliferation rate. Although no recurrently deleterious genomic events were found, some putative tumor suppressors or oncogenes were involved. Mutational signatures indicated potential impaired mismatch function and possible poison contact. Integrated analyses unveiled a group of FNH specific endothelial cells that uniquely expressed SOST and probably had strong interaction with fibroblasts through PDGFB/PDGFRB pathway to promote fibrosis. Notably, in one atypical FNH (patient No.11) with pronounced copy number variations, we observed a unique immune module. Most FNH are benign, but molecularly atypical FNH still exist; endothelial cell derived PDGFB probably promotes the fibrogenic process in FNH.
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Background: A major challenge of psoriasis is its dysfunctional immune niche. Remarkable gaps remain in understanding how immune cell state transitions are linked to clinical outcomes in psoriasis. Thus, there is a pressing need to discover immunomodulatory programs governing psoriasis progression. Methods: Here, by using the state-of-the-art single-cell RNA-sequencing (RNA-seq) data, we observed the unique immune cell profile inside the psoriasis niche compared with the normal skins. Results: In detail, the immunosuppressive T cells such as regulatory T (Treg) cells and CTLA4+ CD8 T cells showed higher infiltration in the psoriasis niche, indicating the immunosuppressive state was imprinted by such disease. Interestingly, unbiased trajectory and pathway enrichment analysis showed that those suppressive T cells potentially showed developmental and metabolic abnormalities. Intercellular crosstalk modeling shows that exhausted CTLA4+ CD8 T cells can send out cytokine signaling via utilizing CXCL13-CXCR3 ligand-receptor pair. We finally quantified the metabolism profile of T cells and strikingly observed their enhanced metabolic activity. Conclusions: Taken together, these data highlight cell-type specific reprogramming within the psoriasis microenvironment and provide evidence for immune-related biomarkers of psoriasis clinical outcome. Our work not only revealed the unique immune ecosystem of psoriasis, but also opened new opportunities for targeting immunometabolism in treating such skin diseases.
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Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous cancer with limited understanding of its classification and tumor microenvironment. Here, by performing single-cell RNA sequencing on 144,878 cells from 14 pairs of iCCA tumors and non-tumor liver tissues, we find that S100P and SPP1 are two markers for iCCA perihilar large duct type (iCCAphl) and peripheral small duct type (iCCApps). S100P + SPP1- iCCAphl has significantly reduced levels of infiltrating CD4+ T cells, CD56+ NK cells, and increased CCL18+ macrophages and PD1+CD8+ T cells compared to S100P-SPP1 + iCCApps. The transcription factor CREB3L1 is identified to regulate the S100P expression and promote tumor cell invasion. S100P-SPP1 + iCCApps has significantly more SPP1+ macrophage infiltration, less aggressiveness and better survival than S100P + SPP1- iCCAphl. Moreover, S100P-SPP1 + iCCApps harbors tumor cells at different status of differentiation, such as ALB + hepatocyte differentiation and ID3+ stemness. Our study extends the understanding of the diversity of tumor cells in iCCA.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos , Linfocitos T CD8-positivos/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Humanos , Transcriptoma , Microambiente Tumoral/genéticaRESUMEN
Liver cancer is the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) accounts for about 85%-90% of all primary liver malignancies. However, only 20-30% of HCC patients are eligible for curative therapy mainly due to the lack of early-detection strategies, highlighting the significance of reliable and accurate biomarkers. The integration of multi-omics became an important tool for biomarker screening and unique alterations in tumor-associated genes, transcripts, proteins, post-translational modifications and metabolites have been observed. We here summarized the novel biomarkers for HCC diagnosis based on multi-omics technology as well as the clinical significance of these potential biomarkers in the early detection of HCC.
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The idea that tumour microenvironment (TME) is organised in a spatial manner will not surprise many cancer biologists; however, systematically capturing spatial architecture of TME is still not possible until recent decade. The past five years have witnessed a boom in the research of high-throughput spatial techniques and algorithms to delineate TME at an unprecedented level. Here, we review the technological progress of spatial omics and how advanced computation methods boost multi-modal spatial data analysis. Then, we discussed the potential clinical translations of spatial omics research in precision oncology, and proposed a transfer of spatial ecological principles to cancer biology in spatial data interpretation. So far, spatial omics is placing us in the golden age of spatial cancer research. Further development and application of spatial omics may lead to a comprehensive decoding of the TME ecosystem and bring the current spatiotemporal molecular medical research into an entirely new paradigm.
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Investigación Biomédica , Análisis Espacial , Microambiente Tumoral/fisiología , Neoplasias , Medicina de PrecisiónRESUMEN
We performed proteogenomic characterization of intrahepatic cholangiocarcinoma (iCCA) using paired tumor and adjacent liver tissues from 262 patients. Integrated proteogenomic analyses prioritized genetic aberrations and revealed hallmarks of iCCA pathogenesis. Aflatoxin signature was associated with tumor initiation, proliferation, and immune suppression. Mutation-associated signaling profiles revealed that TP53 and KRAS co-mutations may contribute to iCCA metastasis via the integrin-FAK-SRC pathway. FGFR2 fusions activated the Rho GTPase pathway and could be a potential source of neoantigens. Proteomic profiling identified four patient subgroups (S1-S4) with subgroup-specific biomarkers. These proteomic subgroups had distinct features in prognosis, genetic alterations, microenvironment dysregulation, tumor microbiota composition, and potential therapeutics. SLC16A3 and HKDC1 were further identified as potential prognostic biomarkers associated with metabolic reprogramming of iCCA cells. This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in iCCA.
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Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/patología , Hígado/patología , Proteogenómica , Neoplasias de los Conductos Biliares/genética , Colangiocarcinoma/genética , Humanos , Mutación/genética , Pronóstico , Proteogenómica/métodos , Proteómica , Microambiente Tumoral/inmunologíaRESUMEN
Liver metastasis, the leading cause of colorectal cancer mortality, exhibits a highly heterogeneous and suppressive immune microenvironment. Here, we sequenced 97 matched samples by using single-cell RNA sequencing and spatial transcriptomics. Strikingly, the metastatic microenvironment underwent remarkable spatial reprogramming of immunosuppressive cells such as MRC1 + CCL18 + M2-like macrophages. We further developed scMetabolism, a computational pipeline for quantifying single-cell metabolism, and observed that those macrophages harbored enhanced metabolic activity. Interestingly, neoadjuvant chemotherapy could block this status and restore the antitumor immune balance in responsive patients, whereas the nonresponsive patients deteriorated into a more suppressive one. Our work described the immune evolution of metastasis and uncovered the black box of how tumors respond to neoadjuvant chemotherapy. SIGNIFICANCE: We present a single-cell and spatial atlas of colorectal liver metastasis and found the highly metabolically activated MRC1 + CCL18 + M2-like macrophages in metastatic sites. Efficient neoadjuvant chemotherapy can slow down such metabolic activation, raising the possibility to target metabolism pathways in metastasis.This article is highlighted in the In This Issue feature, p. 1.
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Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Macrófagos/inmunología , Animales , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Neoplasias Hepáticas/secundario , Ratones , Ratones Endogámicos BALB C , Terapia Neoadyuvante , Metástasis de la Neoplasia , Análisis Espacio-Temporal , Microambiente TumoralRESUMEN
Psoriasis is a common chronic skin disease, characterized by abnormal interplay between hyperproliferative epidermal keratinocytes and self-reactive immune cells with not fully addressed molecular mechanism. N4BP1 (NEDD4-binding protein 1) is considered as an immune regulator for a long time but its physiological role is not determined yet. Here, we found that the expression of N4BP1 in skin was highest among all 54 tested tissues, and its expression was further upregulated in psoriatic skin. N4BP1-deficient mice exhibited normal grossly, but developed severe and prolonged IMQ-induced psoriasis-like disease comparing to controls. N4BP1 mainly expressed in keratinocytes and located on nucleus. Up- but not downregulated genes in N4BP1-deficient skin were specifically enriched in keratinocyte proliferation and differentiation. The proliferation of N4BP1-deficient primary keratinocytes was faster compared to that of controls. The upregulated genes upon ablation of N4BP1 were highly enriched in targets of AP-1 transcription factor. Knocking out N4BP1 resulted in upregulation of JunB and FosB, and conversely, overexpression of N4BP1 greatly reduced their expression. Furthermore, N4BP1 binds with JunB and FosB encoding mRNAs and greatly reduces their stability. In addition, with a high expression in neutrophils, N4BP1 limits survival of neutrophils in blood and infiltration of neutrophils in psoriatic skin by targeting CXCL1, CCL20, and S100A8. These findings demonstrate that N4BP1 controls the proper function of keratinocytes and neutrophils by negatively regulating JunB, FosB, and CXCL1, respectively, and that is critical for psoriasis prevention.