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Interleukin 1 (IL-1) has long been known for its pleiotropic effects on inflammation that plays a complex, and sometimes contrasting, role in different stages of cancer development. As a major proinflammatory cytokine, IL-1ß is mainly expressed by innate immune cells. IL-1α, however, is expressed by various cell types under physiological and pathological conditions. IL-1R1 is the main receptor for both ligands and is expressed by various cell types, including innate and adaptive immune cell types, epithelial cells, endothelial cells, adipocytes, chondrocytes, fibroblasts, etc. IL-1 and IL-1R1 receptor interaction leads to a set of common signaling pathways, mainly the NF-kB and MAP kinase pathways, as a result of complex positive and negative regulations. The variety of cell types with IL-1R1 expression dictates the role of IL-1 signaling at different stages of cancer, which under certain circumstances leads to contrasting roles in tumor development. Recent availability of IL-1R1 conditional knockout mouse model has made it possible to dissect the role of IL-1/IL-1R1 signaling transduction in different cell types within the tumor microenvironment. This chapter will focus on the role of IL-1/IL-1R1 in different cell types within the tumor microenvironment and discuss the potential of targeting this pathway in cancer therapy.
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Interleucina-1/inmunología , Interleucina-1/metabolismo , Transducción de Señal , Microambiente Tumoral , Animales , Humanos , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Interleucina-1/antagonistas & inhibidores , Ratones Noqueados , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
E-cadherin is conventionally considered to be a good prognostic marker in cancer. The loss of E-cadherin is one of the key hallmarks of epithelial-to-mesenchymal transition, a biological process that promotes cancer cell invasiveness and metastasis. Recent evidence has cast doubt on the importance of epithelial-to-mesenchymal transition in metastasis. The availability of protein-level data in the Cancer Genome Atlas allows for the quantitative analysis of protein and prognosis. The prognostic values of E-cadherin and ß-catenin were revisited across 19 cancer types, and high E-cadherin was found to correlate with good prognosis in most cancers. Conversely, higher E-cadherin and ß-catenin correlated with shorter survival in invasive breast carcinoma. Stratifying breast cancers by histologic subtype revealed that the poor prognosis of E-cadherin and ß-catenin proteins was characteristic of infiltrating ductal, but not lobular, carcinomas. To further corroborate the protein findings and examine cellular localization, immunohistochemistry was used for E-cadherin and ß-catenin in 163 breast patient samples from the Iowa cohort. Most previous studies showing that reduced or absent E-cadherin and ß-catenin was inversely associated with tumor stages in ductal carcinomas were confirmed. Taken together, these results lead us to question the prognostic values of E-cadherin and ß-catenin in ductal carcinomas and indicate a complicated role of E-cadherin and ß-catenin in breast cancer progression.
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Antígenos CD/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Cadherinas/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , beta Catenina/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/patología , Femenino , Humanos , Pronóstico , Análisis por Matrices de Proteínas , Tasa de SupervivenciaRESUMEN
Renal cell carcinoma (RCC), the most common form of kidney cancer, is a heterogeneous disease with clear cell RCC (ccRCC) being the most prevalent and aggressive subtype. While most ccRCC tumors have elevated expression of angiopoietin-like4 (ANGPTL4), in our study we identified a significant subset of patients whose cancers show no increase in ANGPTL4 expression. These patients have a worse prognosis compared to the patients with high expression of ANGPTL4. These ANGPTL4-low cancers are characterized by the increased frequency of wild-type Von Hippel-Lindau(WT VHL), a gene that is commonly mutated in ccRCC, and an enrichment for genes associated with lipid metabolism. Using RCC tumor models with WT VHL, we demonstrate that ANGPTL4 behaves as a tumor suppressor. The loss of ANGPTL4 in ccRCC cell lines results in increased tumor growth and colony formation in a lysosomal acid lipase (LAL)-dependent manner, a phenotype rescued by the expression of N-terminus ANGPTL4. At the mechanistic level, the loss of ANGPTL4 increases LAL activity in ccRCC cells. These data suggest that ANGPTL4 enacts its tumor-suppressive effects in ccRCC by regulating LAL activity. Importantly, the identified patient cohort with low ANGPTL4 expression may exhibit increased reliance on lipid metabolism, which can be a point of target for future therapy. SIGNIFICANCE: Our data indicate angiopoietin-like 4 (ANGPTL4) acts as a tumor suppressor in clear cell renal cell carcinoma via regulating lipid metabolism and identifies a cohort of patients with lower expression of ANGPTL4 that are correlated with shorter survival.
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Proteína 4 Similar a la Angiopoyetina , Carcinoma de Células Renales , Neoplasias Renales , Esterol Esterasa , Proteína 4 Similar a la Angiopoyetina/genética , Proteína 4 Similar a la Angiopoyetina/metabolismo , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Humanos , Neoplasias Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Línea Celular Tumoral , Animales , Ratones , Esterol Esterasa/genética , Esterol Esterasa/metabolismo , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Pronóstico , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , FemeninoRESUMEN
Childhood Sjögren's disease represents critically unmet medical needs due to a complete lack of immunological and molecular characterizations. This study presents key immune cell subsets and their interactions in the periphery in childhood Sjögren's disease. Here we show that single-cell RNA sequencing identifies the subsets of IFN gene-enriched monocytes, CD4+ T effector memory, and XCL1+ NK cells as potential key players in childhood Sjögren's disease, and especially in those with recurrent parotitis, which is the chief symptom prompting clinical visits from young children. A unique cluster of monocytes with type I and II IFN-related genes is identified in childhood Sjögren's disease, compared to the age-matched control. In vitro regulatory T cell functional assay demonstrates intact functionality in childhood Sjögren's disease in contrast to reduced suppression in adult Sjögren's disease. Mapping this transcriptomic landscape and interplay of immune cell subsets will expedite the understanding of childhood Sjögren's disease pathogenesis and set the foundation for precision medicine.
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Síndrome de Sjögren , Adulto , Niño , Humanos , Preescolar , Síndrome de Sjögren/genética , Síndrome de Sjögren/diagnóstico , Linfocitos T Reguladores , Perfilación de la Expresión Génica , Transcriptoma , Células Asesinas NaturalesRESUMEN
Interleukin 2 (IL-2) is the first identified cytokine and its interaction with receptors has been known to shape the immune responses in many lymphoid or non-lymphoid tissues for more than four decades. Active T cells are the primary cellular source for IL-2 production and epithelial cells have never been considered the major cellular source of IL-2 under physiological conditions. It is, however, tempting to speculate that epithelial cells could potentially express IL-2 that regulates the intricate interactions between epithelial cells and lymphocytes. Datamining our recently published single-cell RNAseq in the mouse mammary gland identified IL-2 expression in mammary epithelial cells, which is induced by prolactin via the STAT5 signaling pathway. Furthermore, epithelial IL-2 plays a crucial role in maintaining the physiological functions of natural killer (NK) cells within the mammary glands. IL-2 deletion in the mammary epithelial cells leads to a significant reduction in the number and function of NK cells, which in turn results in defective immunosurveillance, expansion of luminal epithelial cells, and tumor development. Interestingly, T cells in the mammary glands are not changed, indicating the specific regulation of NK cells by epithelial IL-2 production. In agreement, we also found that human epithelial cells express IL-2 and NK cells express the highest level of IL2RB among all the immune cells. Here, we provide the first evidence that epithelial cells produce IL-2, which is critical for maintaining the physiological functions of NK cells in immunosurveillance.
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[This corrects the article DOI: 10.1371/journal.pone.0050281.].
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The mismatch repair (MMR) pathway is known as a tumor suppressive pathway and genes involved in MMR are commonly mutated in hereditary colorectal or other cancer types. However, the function of MMR genes/proteins in breast cancer progression and metastasis are largely unknown. We found that MSH2, but not MLH1, is highly enriched in basal-like breast cancer (BLBC) and that its protein expression is inversely correlated with overall survival time (OS). MSH2 expression is frequently elevated due to genomic amplification or gain-of-expression in BLBC, which results in increased MSH2 protein to pair with MSH6 (collectively referred to as MutSα). Genetic deletion of MSH2 or MLH1 results in a contrasting phenotype in metastasis, with MSH2-deletion leading to reduced metastasis and MLH1-deletion to enhanced liver or lung metastasis. Mechanistically, MSH2-deletion induces the expression of a panel of chemokines in BLBC via epigenetic and/or transcriptional regulation, which leads to an immune reactive tumor microenvironment (TME) and elevated immune cell infiltrations. MLH1 is not correlated with chemokine expression and/or immune cell infiltration in BLBC, but its deletion results in strong accumulation of neutrophils that are known for metastasis promotion. Our study supports the differential functions of MSH2 and MLH1 in BLBC progression and metastasis, which challenges the paradigm of the MMR pathway as a universal tumor suppressive mechanism.
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INTRODUCTION: In response to gamma-irradiation (IR)-induced double-strand DNA breaks, cells undergo cell-cycle arrest, allowing time for DNA repair before reentering the cell cycle. G2/M checkpoint activation involves activation of ataxia telangiectasia mutated (ATM)/ATM- and rad3-related (ATR) kinases and inhibition of Cdc25 phosphatases, resulting in inhibition of Cdc2 kinase and subsequent G2/M cell-cycle arrest. Previous studies from our laboratory showed that the G2/M checkpoint activation after IR exposure of MCF-7 breast cancer cells is dependent on the activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signaling. In the present studies, we investigated the role of Ras-related C3 botulinum toxin substrate 1 (Rac1) guanosine triphosphatase (GTPase) in IR-induced G2/M checkpoint response and ERK1/2 activation, as well as in cell survival after IR. METHODS: With Rac1-specific inhibitor, dominant negative mutant Rac1 (N17Rac1) and specific small interfering RNA, the effect of Rac1 on IR-induced G2/M checkpoint response and ERK1/2 activation was examined in human breast cancer cells. In addition, the effect of Rac1 on cell survival after irradiation was assessed by using Rac1-specific inhibitor. RESULTS: IR exposure of MCF-7 breast cancer cells was associated with a marked activation of Rac1 GTPase. Furthermore, inhibition of Rac1 by using specific inhibitor, dominant-negative Rac1 mutant, or specific siRNA resulted in attenuation of IR-induced G2/M arrest and concomitant diminution of IR-induced activation of ATM, ATR, Chk1, and Chk2 kinases, as well as phosphorylation of Cdc2-Tyr15. Moreover, Rac1 inhibition or decreased Rac1 expression also abrogated IR-induced phosphorylation of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) and ERK1/2. Ultimately, inhibition of Rac1 markedly increased cellular sensitivity to IR exposure, which involves induction of apoptosis. CONCLUSION: Studies in this report suggest that Rac1 GTPase plays an essential role in the activation of IR-induced ERK1/2 signaling and subsequent G2/M checkpoint response. Furthermore, results also support a role for Rac1 in promoting cell survival after irradiation treatment.
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Neoplasias de la Mama/radioterapia , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de la radiación , Puntos de Control de la Fase M del Ciclo Celular/efectos de la radiación , Proteína de Unión al GTP rac1/metabolismo , Aminoquinolinas/farmacología , Proteínas de la Ataxia Telangiectasia Mutada , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteína Quinasa CDC2 , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Ciclina B/metabolismo , Quinasas Ciclina-Dependientes , Proteínas de Unión al ADN/metabolismo , Activación Enzimática/efectos de la radiación , Inhibidores Enzimáticos/farmacología , Femenino , Rayos gamma , Humanos , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinas/farmacología , Transducción de Señal , Proteínas Supresoras de Tumor/metabolismo , Tirosina/metabolismo , Proteína de Unión al GTP rac1/antagonistas & inhibidores , Proteína de Unión al GTP rac1/genéticaRESUMEN
In the original publication [...].
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Breast cancer stem cells (BCSCs) constitute a small population of cells within breast cancer and are characterized by their ability to self-renew, differentiate, and recapitulate the heterogeneity of the tumor. Clinically, BCSCs have been correlated with cancer progression, metastasis, relapse, and drug resistance. The tumorigenic roles of BCSCs have been extensively reviewed and will not be the major focus of the current review. Here, we aim to highlight how the crucial intrinsic signaling pathways regulate the fate of BCSCs, including the Wnt, Notch, Hedgehog, and NF-κB signaling pathways, as well as how different cell populations crosstalk with BCSCs within the TME, including adipocytes, endothelial cells, fibroblasts, and immune cells. Based on the molecular and cellular activities of BCSCs, we will also summarize the targeting strategies for BCSCs and related clinical trials. This review will highlight that BCSC development in breast cancer is impacted by both BCSC endogenous signaling and external factors in the TME, which provides an insight into how to establish a comprehensively therapeutic strategy to target BCSCs for breast cancer treatments.
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Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an "atypical" cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis-normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These "atypical" features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients.
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Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis and, within tumors, their upregulation is common and promotes an immunosuppressive microenvironment. Therapeutic strategies that can eliminate Tregs in the tumor (i.e., therapies that do not run the risk of affecting normal tissues), are urgently needed for the development of cancer immunotherapies. Here we report our discovery of B-cell lymphoma extra-large (BCL-XL) as a potential molecular target of tumor-infiltrating (TI) Tregs. We show that pharmacological degradation of BCL-XL using a newly developed platelet-sparing BCL-XL Proteolysis-targeting chimera (PROTAC) induces the apoptosis of TI-Tregs and the activation of TI-CD8+ T cells. Moreover, these activities result in an effective suppression of syngeneic tumor growth in immunocompetent, but not in immunodeficient or CD8+ T cell-depleted mice. Notably, treatment with BCL-XL PROTAC does not cause detectable damage within several normal tissues or thrombocytopenia. These findings identify BCL-XL as a target in the elimination of TI-Tregs as a component of cancer immunotherapies, and that the BCL-XL-specific PROTAC has the potential to be developed as a therapeutic for cancer immunotherapy.
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Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos T Reguladores/metabolismo , Animales , Sistemas CRISPR-Cas/genética , Sistemas CRISPR-Cas/fisiología , Supervivencia Celular/genética , Supervivencia Celular/fisiología , Células Cultivadas , Femenino , Citometría de Flujo , Immunoblotting , Ratones , Ratones Endogámicos C57BL , Proteolisis , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
Regulatory T (Treg) cells are one of the major immunosuppressive cell types in cancer and a potential target for immunotherapy, but targeting tumor-infiltrating (TI) Treg cells has been challenging. Here, using single-cell RNA sequencing of immune cells from renal clear cell carcinoma (ccRCC) patients, we identify two distinct transcriptional fates for TI Treg cells, Fate-1 and Fate-2. The Fate-1 signature is associated with a poorer prognosis in ccRCC and several other solid cancers. CD177, a cell surface protein normally expressed on neutrophil, is specifically expressed on Fate-1 TI Treg cells in several solid cancer types, but not on other TI or peripheral Treg cells. Mechanistically, blocking CD177 reduces the suppressive activity of Treg cells in vitro, while Treg-specific deletion of Cd177 leads to decreased tumor growth and reduced TI Treg frequency in mice. Our results thus uncover a functional CD177+ TI Treg population that may serve as a target for TI Treg-specific immunotherapy.
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Proteínas Ligadas a GPI/metabolismo , Homeostasis , Isoantígenos/metabolismo , Linfocitos Infiltrantes de Tumor/metabolismo , Receptores de Superficie Celular/metabolismo , Linfocitos T Reguladores/metabolismo , Animales , Secuencia de Bases , Carcinogénesis/genética , Carcinogénesis/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Proteínas Ligadas a GPI/deficiencia , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genética , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Ratones Noqueados , Pronóstico , Receptores de Superficie Celular/deficiencia , Análisis de la Célula Individual , Transcripción GenéticaRESUMEN
Obesity is associated with an increased risk of estrogen receptor-positive breast cancer in postmenopausal women and a worse prognosis for all major breast cancer subtypes regardless of menopausal status. While the link between obesity and the pathogenesis of breast cancer is clear, the molecular mechanism of this association is not completely understood due to the complexity of both obesity and breast cancer. The aim of this review is to highlight the association between obesity and breast cancer and discuss the literature, which indicates that this association is due to chronic adipose tissue inflammation. We will discuss the epidemiological data for the association between breast cancer incidence and progression as well as the potential molecular mechanisms for this association. We will focus on the role of inflammation within the adipose tissue during the pathogenesis of breast cancer. A better understanding of how obesity and adipose tissue inflammation affects the pathogenesis of breast cancer will lead to new strategies to reduce breast cancer risk and improve patient outcomes for obese patients.
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Aiming to identify immune molecules with a novel function in cancer pathogenesis, we found the cluster of differentiation 177 (CD177), a known neutrophil antigen, to be positively correlated with relapse-free, metastasis-free, or overall survival in breast cancer. In addition, CD177 expression is correlated with good prognosis in several other solid cancers including prostate, cervical, and lung. Focusing on breast cancer, we found that CD177 is expressed in normal breast epithelial cells and is significantly reduced in invasive cancers. Loss of CD177 leads to hyperproliferative mammary epithelium and contributes to breast cancer pathogenesis. Mechanistically, we found that CD177-deficiency is associated with an increase in ß-catenin signaling. Here we identified CD177 as a novel regulator of mammary epithelial proliferation and breast cancer pathogenesis likely via the modulation of Wnt/ß-catenin signaling pathway, a key signaling pathway involved in multiple cancer types.
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Isoantígenos/metabolismo , Receptores de Superficie Celular/metabolismo , Transducción de Señal/fisiología , beta Catenina/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Diferenciación Celular/fisiología , Línea Celular , Línea Celular Tumoral , Proliferación Celular/fisiología , Células Epiteliales/metabolismo , Femenino , Proteínas Ligadas a GPI/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Células HEK293 , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Vía de Señalización Wnt/fisiologíaRESUMEN
Among all breast cancer types, basal-like breast cancer (BLBC) represents an aggressive subtype that lacks targeted therapy. We and others have found that receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in BLBC and other types of cancer and that ROR1 is significantly correlated with patient prognosis. In addition, using primary patient-derived xenografts (PDXs) and ROR1-knockout BLBC cells, we found that ROR1+ cells form tumors in immunodeficient mice. We developed an anti-ROR1 immunotoxin and found that targeting ROR1 significantly kills ROR1+ cancer cells and slows down tumor growth in ROR1+ xenografts. Our bioinformatics analysis revealed that ROR1 expression is commonly associated with the activation of FGFR-mediated signaling pathway. Further biochemical analysis confirmed that ROR1 stabilized FGFR expression at the posttranslational level by preventing its degradation. CRISPR/Cas9-mediated ROR1 knockout significantly reduced cancer cell invasion at cellular levels by lowering FGFR protein and consequent inactivation of AKT. Our results identified a novel signaling regulation from ROR1 to FGFR and further confirm that ROR1 is a potential therapeutic target for ROR1+ BLBC cells.
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Obesity is a risk factor for breast cancer and also predicts poor clinical outcomes regardless of menopausal status. Contributing to the poor clinical outcomes is the suboptimal efficacy of standard therapies due to dose limiting toxicities and obesity-related complications, highlighting the need to develop novel therapeutic approaches for treating obese patients. We recently found that obesity leads to an increase in tumor-infiltrating macrophages with activated NLRC4 inflammasome and increased interleukin (IL)-1ß production. IL-1ß, in turn, leads to increased angiogenesis and cancer progression. Using Next Generation RNA sequencing, we identified an NLRC4/IL-1ß-dependent upregulation of angiopoietin-like 4 (ANGPTL4), a known angiogenic factor in cancer, in tumors from obese mice. ANGPTL4-deficiency by genetic knockout or treatment with a neutralizing antibody led to a significant reduction in obesity-induced angiogenesis and tumor growth. At a mechanistic level, ANGPTL4 expression is induced by IL-1ß from primary adipocytes in a manner dependent on NF-κB- and MAP kinase-activation, which is further enhanced by hypoxia. This report shows that adipocyte-derived ANGPTL4 drives disease progression under obese conditions and is a potential therapeutic target for treating obese breast cancer patients.
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Proteína 4 Similar a la Angiopoyetina/fisiología , Neoplasias de la Mama/patología , Neovascularización Patológica , Obesidad/complicaciones , Proteína 4 Similar a la Angiopoyetina/genética , Animales , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/genética , Células Cultivadas , Progresión de la Enfermedad , Femenino , Humanos , Inflamasomas/fisiología , Inflamación/etiología , Inflamación/genética , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Desnudos , Ratones Obesos , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Obesidad/genética , Obesidad/metabolismo , Obesidad/patologíaRESUMEN
Immune checkpoints are a diverse set of inhibitory signals to the immune system that play a functional role in adaptive immune response and self-tolerance. Dysregulation of these pathways is a vital mechanism in the avoidance of immune destruction by tumor cells. Immune checkpoint blockade (ICB) refers to targeted strategies to disrupt the tumor co-opted immune suppression to enhance anti-tumor immunity. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) are two immune checkpoints that have the widest range of antibody-based therapies. These therapies have gone from promising approaches to Food and Drug Administration-approved first- and second-line agents for a number of immunogenic cancers. The burgeoning investigations of ICB efficacy in blood and solid cancers have underscored the importance of identifying the predictors of response and resistance to ICB. Identification of response correlates is made complicated by the observations of mixed reactions, or different responses in multiple lesions from the same patient, and delayed responses that can occur over a year after the induction therapy. Factors that can influence response and resistance in ICB can illuminate underlying molecular mechanisms of immune activation and suppression. These same response predictors can guide the identification of patients who would benefit from ICB, reduce off-target immune-relate adverse events, and facilitate the use of combinatorial therapies to increase efficacy. Here we review the underlying principles of immune checkpoint therapy and results of single-agent ICB clinical trials, and summarize the predictors of response and resistance.
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Anticuerpos Monoclonales/uso terapéutico , Resistencia a Antineoplásicos , Neoplasias/tratamiento farmacológico , Anticuerpos Monoclonales/farmacología , Antígeno CTLA-4/antagonistas & inhibidores , Ensayos Clínicos como Asunto , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoterapia/métodos , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Microambiente Tumoral/efectos de los fármacosRESUMEN
Obesity is a growing public health problem and affects 35% US adults. Obesity increases the risk of many cancer types and is associated with poor outcomes. Clinical management of cancer patients has been essentially the same between normal weight and obese individuals. Understanding causal mechanisms by which obesity drives cancer initiation and progression is essential for the development of novel precision therapy for obese cancer patients. One caveat is that various mechanisms have been proposed for different cancer types for their progression under obesity. Since obesity is known to have global impact on inflammation, here we will summarize recent literature and discuss the potential of inflammation being the common causal mechanism to promote cancer promotion across cancer types.
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Inflamación/complicaciones , Neoplasias/patología , Obesidad/complicaciones , Adulto , Animales , Peso Corporal , Progresión de la Enfermedad , Humanos , Inflamación/inmunología , Inflamación/patología , Neoplasias/inmunología , Neoplasias/terapia , Obesidad/epidemiología , Obesidad/inmunología , Estados Unidos/epidemiologíaRESUMEN
Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease worldwide but current treatments remain suboptimal. The role of inflammation in DN has only recently been recognized. It has been shown that the NLRP3-inflammasome contributes to DN development by inducing interleukin (IL)-1ß processing and secretion. In an effort to understand other IL-1ß activating mechanism during DN development, we examined the role of the NLRC4-inflammasome in DN and found that NLRC4 is a parallel mechanism, in addition to the NLRP3-inflammasome, to induce pro-IL-1ß processing and activation. We found that the expression of NLRC4 is elevated in DN kidneys. NLRC4-deficiency results in diminished DN disease progression, as manifested by a decrease in blood glucose and albumin excretion, as well as preserved renal histology. We further found that DN kidneys have increased F4/80+ macrophages, increased IL-1ß production, and other signaling pathways related to kidney pathology such as activation of NF-κB and MAP kinase pathways, all of which were rescued by NLRC4-deficiency. This study demonstrates NLRC4-driven IL-1ß production as critical for the progression of DN, which underscores the importance to target this pathway to alleviate this devastating disease.