RESUMO
Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2+) Treg cells that are enriched in males and a previously uncharacterized population of C-X-C motif chemokine receptor 3-positive (CXCR3+) Treg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2+ VAT Treg cells but repress CXCR3+ Treg cells. Conversely, the differentiation of CXCR3+ Treg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2+ Treg cells. Finally, we demonstrate that ST2+ Treg cells preserve glucose homeostasis, whereas CXCR3+ Treg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT Treg cell types with unique context- and sex-specific functions.
Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1 , Linfócitos T Reguladores , Feminino , Masculino , Humanos , Gordura Intra-Abdominal , Citocinas , Inflamação , GlucoseRESUMO
Tissue-resident memory T (TRM) cells are non-recirculating cells that exist throughout the body. Although TRM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze TRM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM cell function, durability and malleability. We find that unequal responsiveness to TGFß is a major driver of this diversity. Notably, dampened TGFß signaling results in CD103- TRM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFß-responsive CD103+ TRM counterparts. Furthermore, whereas CD103- TRM cells readily modified their phenotype upon relocation, CD103+ TRM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for TRM cell development, tissue adaptation of these cells confers discrete functional properties such that TRM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Plasticidade Celular/imunologia , Microambiente Celular/imunologia , Memória Imunológica/imunologia , Animais , Antígenos CD/imunologia , Linfócitos T CD8-Positivos/citologia , Feminino , Cadeias alfa de Integrinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
CD8+ T cells responding to chronic infections or tumors acquire an 'exhausted' state associated with elevated expression of inhibitory receptors, including PD-1, and impaired cytokine production. Exhausted T cells are continuously replenished by T cells with precursor characteristics that self-renew and depend on the transcription factor TCF1; however, their developmental requirements are poorly understood. In the present study, we demonstrate that high antigen load promoted the differentiation of precursor T cells, which acquired hallmarks of exhaustion within days of infection, whereas early effector cells retained polyfunctional features. Early precursor T cells showed epigenetic imprinting characteristic of T cell receptor-dependent transcription factor binding and were restricted to the generation of cells displaying exhaustion characteristics. Transcription factors BACH2 and BATF were key regulators with opposing functions in the generation of early precursor T cells. Overall, we demonstrate that exhaustion manifests first in TCF1+ precursor T cells and is propagated subsequently to the pool of antigen-specific T cells.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Células Precursoras de Linfócitos T/imunologia , Animais , Diferenciação Celular , Autorrenovação Celular , Células Cultivadas , Doença Crônica , Anergia Clonal , Epigênese Genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos TRESUMO
Antigen-specific CD8+ T cells in chronic viral infections and tumors functionally deteriorate, a process known as exhaustion. Exhausted T cells are sustained by precursors of exhausted (Tpex) cells that self-renew while continuously generating exhausted effector (Tex) cells. However, it remains unknown how Tpex cells maintain their functionality. Here, we demonstrate that Tpex cells sustained mitochondrial fitness, including high spare respiratory capacity, while Tex cells deteriorated metabolically over time. Tpex cells showed early suppression of mTOR kinase signaling but retained the ability to activate this pathway in response to antigen receptor signals. Early transient mTOR inhibition improved long-term T cell responses and checkpoint inhibition. Transforming growth factor-ß repressed mTOR signaling in exhausted T cells and was a critical determinant of Tpex cell metabolism and function. Overall, we demonstrate that the preservation of cellular metabolism allows Tpex cells to retain long-term functionality to sustain T cell responses during chronic infection.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Metabolismo Energético/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/metabolismo , Transdução de Sinais/imunologiaRESUMO
CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality-which is referred to as T cell exhaustion1,2-is maintained by precursors of exhausted T (TPEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1- exhausted effector T cells3-6. Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L+ TPEX cells. The transcription factor MYB is not only essential for the development of CD62L+ TPEX cells and maintenance of the antiviral CD8+ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L+ TPEX cells and depends on MYB. Our findings identify CD62L+ TPEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.
Assuntos
Linfócitos T CD8-Positivos , Receptor de Morte Celular Programada 1 , Proteínas Proto-Oncogênicas c-myb , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Autorrenovação Celular , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Imunoterapia , Selectina L/metabolismo , Células Precursoras de Linfócitos T/citologia , Células Precursoras de Linfócitos T/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-myb/metabolismo , Vírus/imunologiaRESUMO
Adipose tissue is an energy store and a dynamic endocrine organ1,2. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism3,4. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes5,6. Regulatory T (Treg) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT7-9. Here we uncover pronounced sexual dimorphism in Treg cells in the VAT. Male VAT was enriched for Treg cells compared with female VAT, and Treg cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of Treg cells via the CCL2-CCR2 axis. Androgen regulated the differentiation of a unique IL-33-producing stromal cell population specific to the male VAT, which paralleled the local expansion of Treg cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident Treg cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in Treg cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.
Assuntos
Hormônios Esteroides Gonadais/metabolismo , Gordura Intra-Abdominal/imunologia , Caracteres Sexuais , Linfócitos T Reguladores/imunologia , Androgênios/metabolismo , Animais , Quimiocina CCL2/imunologia , Cromatina/genética , Feminino , Regulação da Expressão Gênica , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-33/imunologia , Gordura Intra-Abdominal/metabolismo , Masculino , Camundongos , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , RNA-Seq , Receptores CCR2/metabolismo , Células Estromais/citologia , Células Estromais/imunologia , Células Estromais/metabolismo , Linfócitos T Reguladores/metabolismo , Transcrição GênicaRESUMO
BACKGROUND: RNA sequencing is currently the method of choice for genome-wide profiling of gene expression. A popular approach to quantify expression levels of genes from RNA-seq data is to map reads to a reference genome and then count mapped reads to each gene. Gene annotation data, which include chromosomal coordinates of exons for tens of thousands of genes, are required for this quantification process. There are several major sources of gene annotations that can be used for quantification, such as Ensembl and RefSeq databases. However, there is very little understanding of the effect that the choice of annotation has on the accuracy of gene expression quantification in an RNA-seq analysis. RESULTS: In this paper, we present results from our comparison of Ensembl and RefSeq human annotations on their impact on gene expression quantification using a benchmark RNA-seq dataset generated by the SEQC consortium. We show that the use of RefSeq gene annotation models led to better quantification accuracy, based on the correlation with ground truths including expression data from >800 real-time PCR validated genes, known titration ratios of gene expression and microarray expression data. We also found that the recent expansion of the RefSeq annotation has led to a decrease in its annotation accuracy. Finally, we demonstrated that the RNA-seq quantification differences observed between different annotations were not affected by the use of different normalization methods. CONCLUSION: In conclusion, our study found that the use of the conservative RefSeq gene annotation yields better RNA-seq quantification results than the more comprehensive Ensembl annotation. We also found that, surprisingly, the recent expansion of the RefSeq database, which was primarily driven by the incorporation of sequencing data into the gene annotation process, resulted in a reduction in the accuracy of RNA-seq quantification.
Assuntos
Anotação de Sequência Molecular , Sequência de Bases , Humanos , RNA-Seq , Análise de Sequência de RNA/métodos , Sequenciamento do ExomaRESUMO
Interleukin-36 gamma (IL-36G) is a member of the IL-36 subfamily of cytokines and acts as a potent driver of inflammation. IL-36G has been extensively characterized in the pathogenesis of psoriasis and has been recently described to play roles in wound healing particularly in the gastrointestinal tract. However, the effects of IL-36G during cancer development including gastric cancer remain unexplored. Here, we show that IL-36G induced ERK1/2 activation in AGS, MKN1 and MKN45 human gastric cancer cell lines. Moreover, IL-36G induced colony formation, migration and invasion of these gastric cancer cell lines that was inhibited by the natural antagonist, IL-36 receptor antagonist (RA). Interrogation of TCGA stomach adenocarcinoma patient datasets revealed highly elevated IL-36G gene expression in human gastric cancer compared to normal tissue independent of tumor stage, and high IL-36G expression corresponded with poorer patient survival. Collectively, our results indicate for the first time that IL-36G supports a neoplastic phenotype in human gastric cancer cells.
Assuntos
Adenocarcinoma , Neoplasias Gástricas , Adenocarcinoma/genética , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Transdução de Sinais , Neoplasias Gástricas/patologiaRESUMO
In order to advance our understanding of colorectal cancer (CRC) development and progression, biomedical researchers have generated large amounts of OMICS data from CRC patient samples and representative cell lines. However, these data are deposited in various repositories or in supplementary tables. A database which integrates data from heterogeneous resources and enables analysis of the multidimensional data sets, specifically pertaining to CRC is currently lacking. Here, we have developed Colorectal Cancer Atlas (http://www.colonatlas.org), an integrated web-based resource that catalogues the genomic and proteomic annotations identified in CRC tissues and cell lines. The data catalogued to-date include sequence variations as well as quantitative and non-quantitative protein expression data. The database enables the analysis of these data in the context of signaling pathways, protein-protein interactions, Gene Ontology terms, protein domains and post-translational modifications. Currently, Colorectal Cancer Atlas contains data for >13 711 CRC tissues, >165 CRC cell lines, 62 251 protein identifications, >8.3 million MS/MS spectra, >18 410 genes with sequence variations (404 278 entries) and 351 pathways with sequence variants. Overall, Colorectal Cancer Atlas has been designed to serve as a central resource to facilitate research in CRC.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Bases de Dados Genéticas , Genômica , Proteômica , Linhagem Celular Tumoral , Humanos , Anotação de Sequência Molecular , Mutação , Processamento de Proteína Pós-Traducional , Estrutura Terciária de ProteínaRESUMO
PURPOSE: Mental health challenges are highly prevalent in African migrants. However, understanding of mental health outcomes in first-generation voluntary African migrants is limited, despite the unique challenges faced by this migrant subgroup. This review aimed to synthesize the literature to understand the mental health challenges, help-seeking behavior, and the relationship between mental health and mental health help-seeking behavior in first-generation voluntary African migrants living outside Africa. METHODS: Medline Complete, EMBASE, CINAHL Complete, and APA PsychINFO were searched for studies published between January 2012 to December 2023. Retrieved articles were processed, data from selected articles were extracted and synthesized to address the study aims, and included studies were evaluated for risk of bias. RESULTS: Eight studies were included, including four quantitative and four qualitative studies, which focused on women with postnatal depression. Mental health challenges reported in the quantitative studies were depression, interpersonal disorders, and work-related stress. Risk (e.g., neglect from health professionals and lack of social/spousal support) and protective (e.g., sensitivity of community services and faith) factors associated with mental health were identified. Barriers (e.g., cultural beliefs about mental health and racial discrimination) and facilitators (sensitizing African women about mental health) of mental health help-seeking behavior were also identified. No significant relationship was reported between mental health and mental health help-seeking behavior, and the risk of bias results indicated some methodological flaws in the studies. CONCLUSION: This review shows the dearth of research focusing on mental health and help-seeking behavior in this subgroup of African migrants. The findings highlight the importance of African migrants, especially mothers with newborns, examining cultural beliefs that may impact their mental health and willingness to seek help. Receiving countries should also strive to understand the needs of first-generation voluntary African migrants living abroad and offer mental health support that is patient-centered and culturally sensitive.
Assuntos
Comportamento de Busca de Ajuda , Serviços de Saúde Mental , Migrantes , Humanos , Saúde Mental , Migrantes/psicologiaRESUMO
Deregulation of the Hippo pathway is a driver for cancer progression and treatment resistance. In the context of gastric cancer, YAP1 is a biomarker for poor patient prognosis. Although genomic tumor profiling provides information of Hippo pathway activation, the present study demonstrates that inhibition of Yap1 activity has anti-tumor effects in gastric tumors driven by oncogenic mutations and inflammatory cytokines. We show that Yap1 is a key regulator of cell metabolism, proliferation, and immune responses in normal and neoplastic gastric epithelium. We propose that the Hippo pathway is targetable across gastric cancer subtypes and its therapeutic benefits are likely to be mediated by both cancer cell-intrinsic and -extrinsic mechanisms.
Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Microambiente Tumoral , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Via de Sinalização Hippo , Fator de Transcrição STAT3/metabolismoRESUMO
Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of KrasG12D;Pik3caH1047R or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047R is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions. An additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with the poorer survival of patients with high IL-6 expression, we identify IL-6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.
RESUMO
Cancer immunotherapies have demonstrated remarkable success; however, the majority of patients do not respond or develop resistance. Here, we conduct epigenetic gene-targeted CRISPR-Cas9 screens to identify epigenomic factors that limit CD8+ T cell-mediated anti-tumor immunity. We identify that PRMT1 suppresses interferon gamma (Ifnγ)-induced MHC-I expression, thus dampening CD8+ T cell-mediated killing. Indeed, PRMT1 knockout or pharmacological targeting of type I PRMT with the clinical inhibitor GSK3368715 enhances Ifnγ-induced MHC-I expression through elevated STAT1 expression and activation, while re-introduction of PRMT1 in PRMT1-deficient cells reverses this effect. Importantly, loss of PRMT1 enhances the efficacy of anti-PD-1 immunotherapy, and The Cancer Genome Atlas analysis reveals that PRMT1 expression in human melanoma is inversely correlated with expression of human leukocyte antigen molecules, infiltration of CD8+ T cells, and overall survival. Taken together, we identify PRMT1 as a negative regulator of anti-tumor immunity, unveiling clinical type I PRMT inhibitors as immunotherapeutic agents or as adjuncts to existing immunotherapies.
Assuntos
Linfócitos T CD8-Positivos , Melanoma , Humanos , Linfócitos T CD8-Positivos/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Imunidade Celular , Interferon gama/metabolismo , Melanoma/patologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismoRESUMO
The transcription factor EHF is highly expressed in the lactating mammary gland, but its role in mammary development and tumorigenesis is not fully understood. Utilizing a mouse model of Ehf deletion, herein, we demonstrate that loss of Ehf impairs mammary lobuloalveolar differentiation at late pregnancy, indicated by significantly reduced levels of milk genes and milk lipids, fewer differentiated alveolar cells, and an accumulation of alveolar progenitor cells. Further, deletion of Ehf increased proliferative capacity and attenuated prolactin-induced alveolar differentiation in mammary organoids. Ehf deletion also increased tumor incidence in the MMTV-PyMT mammary tumor model and increased the proliferative capacity of mammary tumor organoids, while low EHF expression was associated with higher tumor grade and poorer outcome in luminal A and basal human breast cancers. Collectively, these findings establish EHF as a non-redundant regulator of mammary alveolar differentiation and a putative suppressor of mammary tumorigenesis.
Assuntos
Neoplasias da Mama , Diferenciação Celular , Glândulas Mamárias Animais , Animais , Feminino , Camundongos , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/citologia , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Humanos , Carcinogênese/patologia , Carcinogênese/metabolismo , Carcinogênese/genética , Linhagem da Célula , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proliferação de Células , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/citologia , Gravidez , LactaçãoRESUMO
Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here, we report the pro-tumorigenic properties of the crosstalk between intestinal tuft cells and type 2 innate lymphoid cells (ILC2) that is evolutionarily optimized for epithelial remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) drives ILC2 activation, inducing the release of IL13 and promoting epithelial tuft cell hyperplasia. While the resulting tuft cell - ILC2 feed-forward circuit promotes gastric metaplasia and tumor formation, genetic depletion of tuft cells or ILC2s, or therapeutic targeting of IL13 or IL25 alleviates these pathologies in mice. In gastric cancer patients, tuft cell and ILC2 gene signatures predict worsening survival in intestinal-type gastric cancer where ~40% of the corresponding cancers show enriched co-existence of tuft cells and ILC2s. Our findings suggest a role for ILC2 and tuft cells, along with their associated cytokine IL13 and IL25 as gatekeepers and enablers of metaplastic transformation and gastric tumorigenesis, thereby providing an opportunity to therapeutically inhibit early-stage gastric cancer through repurposing antibody-mediated therapies.
Assuntos
Imunidade Inata , Neoplasias Gástricas , Humanos , Camundongos , Animais , Interleucina-13/metabolismo , Neoplasias Gástricas/patologia , Linfócitos/metabolismo , Hiperplasia/metabolismo , Metaplasia/metabolismoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a low 5-year survival rate and is associated with poor response to therapy. Elevated expression of the myeloid-specific hematopoietic cell kinase (HCK) is observed in PDAC and correlates with reduced patient survival. To determine whether aberrant HCK signaling in myeloid cells is involved in PDAC growth and metastasis, we established orthotopic and intrasplenic PDAC tumors in wild-type and HCK knockout mice. Genetic ablation of HCK impaired PDAC growth and metastasis by inducing an immune-stimulatory endotype in myeloid cells, which in turn reduced the desmoplastic microenvironment and enhanced cytotoxic effector cell infiltration. Consequently, genetic ablation or therapeutic inhibition of HCK minimized metastatic spread, enhanced the efficacy of chemotherapy, and overcame resistance to anti-PD1, anti-CTLA4, or stimulatory anti-CD40 immunotherapy. Our results provide strong rationale for HCK to be developed as a therapeutic target to improve the response of PDAC to chemo- and immunotherapy.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas c-hck , Animais , Carcinoma Ductal Pancreático/genética , Camundongos , Células Mieloides/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-hck/genética , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Although immunotherapy has revolutionized cancer treatment, many immunogenic tumors remain refractory to treatment. This can be largely attributed to an immunologically "cold" tumor microenvironment characterized by an accumulation of immunosuppressive myeloid cells and exclusion of activated T cells. Here, we demonstrate that genetic ablation or therapeutic inhibition of the myeloid-specific hematopoietic cell kinase (HCK) enables activity of antagonistic anti-programmed cell death protein 1 (anti-PD1), anti-CTLA4, or agonistic anti-CD40 immunotherapies in otherwise refractory tumors and augments response in treatment-susceptible tumors. Mechanistically, HCK ablation reprograms tumor-associated macrophages and dendritic cells toward an inflammatory endotype and enhances CD8+ T cell recruitment and activation when combined with immunotherapy in mice. Meanwhile, therapeutic inhibition of HCK in humanized mice engrafted with patient-derived xenografts counteracts tumor immunosuppression, improves T cell recruitment, and impairs tumor growth. Collectively, our results suggest that therapeutic targeting of HCK activity enhances response to immunotherapy by simultaneously stimulating immune cell activation and inhibiting the immunosuppressive tumor microenvironment.
RESUMO
IL11 is a member of the IL6 family of cytokines and signals through its cognate receptor subunits, IL11RA and glycoprotein 130 (GP130), to elicit biological responses via the JAK/STAT signaling pathway. IL11 contributes to cancer progression by promoting the survival and proliferation of cancer cells, but the potential immunomodulatory properties of IL11 signaling during tumor development have thus far remained unexplored. Here, we have characterized a role for IL11 in regulating CD4+ T cell-mediated antitumor responses. Absence of IL11 signaling impaired tumor growth in a sporadic mouse model of colon cancer and syngeneic allograft models of colon cancer. Adoptive bone marrow transfer experiments and in vivo depletion studies demonstrated that the tumor-promoting activity of IL11 was mediated through its suppressive effect on host CD4+ T cells in the tumor microenvironment. Indeed, when compared with Il11ra-proficient CD4+ T cells associated with MC38 tumors, their Il11ra-deficient counterparts displayed elevated expression of mRNA encoding the antitumor mediators IFNγ and TNFα. Likewise, IL11 potently suppressed the production of proinflammatory cytokines (IFNγ, TNFα, IL6, and IL12p70) by CD4+ T cells in vitro, which we corroborated by RNAscope analysis of human colorectal cancers, where IL11RAhigh tumors showed less IFNG and CD4 expression than IL11RAlow tumors. Therefore, our results ascribe a tumor cell-extrinsic immunomodulatory role to IL11 during colon cancer development that could be amenable to an anticytokine-based therapy.See related Spotlight by van der Burg, p. 724.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Neoplasias do Colo/imunologia , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Interleucina-11/metabolismo , Animais , Antígenos CD4/análise , Antígenos CD4/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular Tumoral , Colo/imunologia , Colo/patologia , Neoplasias do Colo/patologia , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Interferon gama/análise , Interferon gama/metabolismo , Subunidade alfa de Receptor de Interleucina-11/análise , Subunidade alfa de Receptor de Interleucina-11/genética , Camundongos , Camundongos Knockout , Neoplasias de Tecido Ósseo , Receptores de Interleucina-11/metabolismo , Microambiente Tumoral/imunologiaRESUMO
The concept that extracellular vesicles (EVs) from the diet can be absorbed by the intestinal tract of the consuming organism, be bioavailable in various organs, and in-turn exert phenotypic changes is highly debatable. Here, we isolate EVs from both raw and commercial bovine milk and characterize them by electron microscopy, nanoparticle tracking analysis, western blotting, quantitative proteomics and small RNA sequencing analysis. Orally administered bovine milk-derived EVs survive the harsh degrading conditions of the gut, in mice, and is subsequently detected in multiple organs. Milk-derived EVs orally administered to mice implanted with colorectal and breast cancer cells reduce the primary tumor burden. Intriguingly, despite the reduction in primary tumor growth, milk-derived EVs accelerate metastasis in breast and pancreatic cancer mouse models. Proteomic and biochemical analysis reveal the induction of senescence and epithelial-to-mesenchymal transition in cancer cells upon treatment with milk-derived EVs. Timing of EV administration is critical as oral administration after resection of the primary tumor reverses the pro-metastatic effects of milk-derived EVs in breast cancer models. Taken together, our study provides context-based and opposing roles of milk-derived EVs as metastasis inducers and suppressors.