RESUMO
Increased T helper (Th)1/Th17 immune responses are a hallmark of Crohn's disease (CD) immunopathogenesis. CD90+ (myo-)fibroblasts (MFs) are abundant cells in the normal (N) intestinal mucosa contributing to mucosal tolerance via suppression of Th1 cell activity through cell surface membrane-bound PD-L1 (mPD-L1). CD-MFs have a decreased level of mPD-L1. Consequently, mPD-L1-mediated suppression of Th1 cells by CD-MFs is decreased, yet the mechanism responsible for the reduction in mPDL-1 is unknown. Increased expression of matrix metalloproteinases (MMPs) has been reported in CD. Herein we observed that when compared to N- and ulcerative colitis (UC)-MFs, CD-MFs increase in LPS-inducible levels of MMP-7 and -9 with a significant increase in both basal and inducible MMP-10. A similar pattern of MMP expression was observed in the CD-inflamed mucosa. Treatment of N-MFs with a combination of recombinant human MMP-7, -9 and -10 significantly decreased mPD-L1. In contrast, inhibition of MMP activity with MMP inhibitors or anti-MMP-10 neutralizing antibodies restores mPD-L1 on CD-MFs. CD-MFs demonstrated reduced capacity to suppress Th1 and Th17 responses from activated CD4+ T cells. By contrast, supplementation of the CD-MF:T-cell co-cultures with MMP inhibitors or anti-MMP neutralizing antibodies restored the CD-MF-mediated suppression. Our data suggest that (i) increased MMP-10 expression by CD-MFs and concomitant cleavage of PD-L1 from the surface of CD-MFs are likely to be one of the factors contributing to the decrease of mPD-L1-mediated suppression of Th1/Th17 cells in CD; and (ii) MMPs are likely to have a significant role in the intestinal mucosal immune responses.
Assuntos
Antígeno B7-H1/metabolismo , Membrana Celular/metabolismo , Doença de Crohn/metabolismo , Fibroblastos/metabolismo , Metaloproteinases da Matriz/metabolismo , Antígenos Thy-1/metabolismo , Antígeno B7-H1/imunologia , Membrana Celular/imunologia , Doença de Crohn/imunologia , Doença de Crohn/patologia , Feminino , Fibroblastos/imunologia , Fibroblastos/patologia , Humanos , Metaloproteinases da Matriz/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Antígenos Thy-1/imunologiaRESUMO
Chronic inflammation is a risk factor for colorectal cancer. The MAPK-activated protein kinase 2 (MK2) pathway controls multiple cellular processes including p38-dependent inflammation. This is the first study to investigate the role of MK2 in development of colitis-associated colon cancer (CAC). Herein, we demonstrate that MK2(-/-) mice are highly resistant to neoplasm development when exposed to AOM/DSS, while wild type (WT) C57BL/6 develop multiple neoplasms with the same treatment. MK2-specific cytokines IL-1, IL-6 and TNF-α were substantially decreased in AOM/DSS treated MK2(-/-) mouse colon tissues compared with WT mice, which coincided with a marked decrease in macrophage influx. Restoring MK2-competent macrophages by injecting WT bone marrow derived macrophages into MK2(-/-) mice led to partial restoration of inflammatory cytokine production with AOM/DSS treatment; however, macrophages were not sufficient to induce neoplasm development. These results indicate that MK2 functions as an inflammatory regulator to promote colonic neoplasm development and may be a potential target for CAC.
Assuntos
Neoplasias Colorretais/etiologia , Inflamação/complicações , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Neoplasias Colorretais/prevenção & controle , Citocinas/biossíntese , Feminino , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/antagonistas & inibidoresRESUMO
BACKGROUND: The United States notoriously has one of the highest rates of incarceration in the world, yet scant attention to the health care needs of those incarcerated exists within laboratory medicine and pathology training and education. This article explores health disparities among incarcerated and released individuals regarding diagnostic laboratory testing and pathology services. METHODS: A literature search was conducted for articles published between 2002 and 2023 using keywords including "healthcare," "incarcerated," "laboratory services," "pathology services," and "health insurance for prisoners." Central themes were extracted and discussed to reveal the realities of health care during and after release from incarceration. Excluded from the analysis were articles about the immediate or extended family of incarcerated persons. RESULTS: Incarcerated individuals have an increased risk for the development and exacerbation of communicable and noncommunicable diseases and mental health disorders, which results in exceedingly high morbidity and mortality rates. CONCLUSION: Policy changes are needed to mitigate disparities and improve health outcomes for incarcerated and released persons. Central to these disparities is decreased access to laboratory and pathology services, impeded by inadequate health care funding for these carceral institutions. Providing additional funding to the carceral system's health care budget is necessary to improve access to pathology and laboratory services.
RESUMO
BACKGROUND: Perineural invasion (PNI) and nerve density within the tumor microenvironment (TME) have long been associated with worse outcomes in head and neck squamous cell carcinoma (HNSCC). This prompted an investigation into how nerves within the tumor microenvironment affect the adaptive immune system and tumor growth. METHODS: We used RNA sequencing analysis of human tumor tissue from a recent HNSCC clinical trial, proteomics of human nerves from HNSCC patients, and syngeneic orthotopic murine models of HPV-unrelated HNSCC to investigate how sensory nerves modulate the adaptive immune system. FINDINGS: Calcitonin gene-related peptide (CGRP) directly inhibited CD8 T cell activity in vitro, and blocking sensory nerve function surgically, pharmacologically, or genetically increased CD8 and CD4 T cell activity in vivo. CONCLUSIONS: Our data support sensory nerves playing a role in accelerating tumor growth by directly acting on the adaptive immune system to decrease Th1 CD4 T cells and activated CD8 T cells in the TME. These data support further investigation into the role of sensory nerves in the TME of HNSCC and points toward the possible treatment efficacy of blocking sensory nerve function or specifically inhibiting CGRP release or activity within the TME to improve outcomes. FUNDING: 1R01DE028282-01, 1R01DE028529-01, 1P50CA261605-01 (to S.D.K.), 1R01CA284651-01 (to S.D.K.), and F31 DE029997 (to L.B.D.).
Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Neoplasias de Cabeça e Pescoço , Animais , Humanos , Camundongos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente TumoralRESUMO
OBJECTIVES: To present a patient with the first case of NTM (nontuberculous mycobacteria) infection of the larynx extending to cervical trachea, and the first case of subglottic stenosis associated with an NTM infection. METHODS: Case report and review of the literature. RESULTS: A 68-year-old female with history of prior smoking, gastroesophageal reflux disease, asthma, bronchiectasis, and tracheobronchomalacia presented with a 3-month history of shortness of breath, exertional inspiratory stridor, and hoarseness. Flexible laryngoscopy demonstrated ulceration of medial aspect of right vocal fold and subglottic tissue abnormality with crusting and ulceration extending through the upper trachea. Microdirect laryngoscopy with tissue biopsies and carbon dioxide (CO2) laser ablation of disease completed, and intraoperative culture revealed positive Aspergillus and acid-fast bacilli with Mycobacterium abscessus (type of NTM). Patient began antimicrobial treatment of cefoxitin, imipenem, amikacin, azithromycin, clofazimine, and itraconazole. Fourteen months after initial presentation, patient developed subglottic stenosis with limited extension into the proximal trachea prompting CO2 laser incision, balloon dilation, and steroid injection of the subglottic stenosis. Patient remains disease free without further subglottic stenosis. CONCLUSION: Laryngeal NTM infections are exceedingly rare. Failure to consider NTM infection in the differential diagnosis when presented with an ulcerative, exophytic mass in patients with increased risk factors (structural lung disease, Pseudomonas colonization, chronic steroid use, prior NTM positivity) may result in insufficient tissue evaluation, delayed diagnosis, and disease progression.
Assuntos
Laringe , Infecções por Mycobacterium não Tuberculosas , Feminino , Humanos , Idoso , Traqueia , Constrição Patológica , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/terapia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas , EsteroidesRESUMO
BACKGROUND: Oral squamous cell carcinoma (OSCC) is a devastating disease most often associated with tobacco consumption that induces a field of mutations from which a tumor arises. Identification of ways to prevent the emergence of cancer in high-risk patients is an ultimate goal for combatting all types of cancer, including OSCC. METHODS: Our study employs a mouse model of tongue carcinogenesis induced by tobacco carcinogen mimetic, 4-nitroquinoline 1-oxide (4NQO), to establish tongue dysplasia and OSCC. We use conventional histology, immunohistochemistry, multispectral imaging, mass cytometry, novel cell lines, pharmaceutical inhibition of PI3Kγ, T-cell suppression assays and mouse transplant models in our functional experimentation. RESULTS: In our study, we identify Ly6G+ granulocytes as the most abundant immune cell type in a model of tongue carcinogenesis induced by tobacco carcinogen mimetic 4NQO. Targeting Ly6G+ granulocytes with a pharmacologic inhibitor of PI3Kγ, an isoform of PI3K exclusively expressed by myeloid cells, resulted in reduced tongue dysplasia severity, and reduced rates of OSCC. Importantly, we performed functional assays with the Ly6G+ granulocytes induced in cell line models of 4NQO carcinogenesis to demonstrate that these granulocytes have increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) activity against T-cell proliferation and these PMN-MDSCs play a functional role in promoting tumor formation by inhibiting tumor regression in a PI3Kγ-dependent manner. CONCLUSIONS: Overall, our data suggest that recruitment of PMN-MDSCs to sites of dysplasia is critical to immune suppression of CD8 T cells, thereby permitting malignancy, and PI3Kγ inhibitors are one mechanism to reduce PMN-MDSC recruitment, immunosuppression and tumorigenesis in OSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Células Supressoras Mieloides , Humanos , Animais , Camundongos , Fosfatidilinositol 3-Quinase , Carcinoma de Células Escamosas/induzido quimicamente , Neoplasias Bucais/induzido quimicamente , Carcinogênese , Carcinógenos/toxicidade , Carcinoma de Células Escamosas de Cabeça e Pescoço , FosfatidilinositóisRESUMO
Patient safety education is a mandated Common Program Requirement of the Accreditation Council for Graduate Medical Education and for the Royal College of Physicians and Surgeons of Canada in all medical residency and fellowship programs. Although many hospitals and healthcare environments have general patient safety education tools for trainees, few to none focus on the unique training milieu of pathologists, including a mix of highly automated and manual error-prone processes, frequent multiplicity of events, and lack of direct patient relationships for error disclosure. We established a national Association of Pathology Chairs-Program Directors Section Workgroup focused on patient safety education for pathology trainees entitled Training Residents in Patient Safety (TRIPS). TRIPS included diverse representatives from across the United States, as well as representatives from pathology organizations including the American Board of Pathology, the American Society for Clinical Pathology, the United States and Canadian Academy of Pathology, the College of American Pathologists, and the Society to Improve Diagnosis in Medicine. Objectives of the workgroup included developing a standardized patient safety curriculum, designing teaching and assessment tools, and refining them with pilot sites. Here we report the establishment of TRIPS as well as data from national needs assessment of Program Directors across the country, who confirmed the need for a standardized patient safety curriculum.
RESUMO
In the setting of conventional radiation therapy, even when combined with immunotherapy, head and neck cancer often recurs locally and regionally. Elective nodal irradiation (ENI) is commonly employed to decrease regional recurrence. Given our developing understanding that immune cells are radio-sensitive, and that T cell priming occurs in the draining lymph nodes (DLNs), we hypothesize that radiation therapy directed at the primary tumor only will increase the effectiveness of immunotherapies. We find that ENI increases local, distant, and metastatic tumor growth. Multi-compartmental analysis of the primary/distant tumor, the DLNs, and the blood shows that ENI decreases the immune response systemically. Additionally, we find that ENI decreases antigen-specific T cells and epitope spreading. Treating the primary tumor with radiation and immunotherapy, however, fails to reduce regional recurrence, but this is reversed by either concurrent sentinel lymph node resection or irradiation. Our data support using lymphatic sparing radiation therapy for head and neck cancer.
Assuntos
Neoplasias de Cabeça e Pescoço , Linfonodo Sentinela , Humanos , Neoplasias de Cabeça e Pescoço/radioterapia , Terapia Combinada , Excisão de Linfonodo , ImunoterapiaRESUMO
Five-year survival for human papilloma virus-unrelated head and neck squamous cell carcinomas remain below 50%. We assessed the safety of administering combination hypofractionated stereotactic body radiation therapy with single-dose durvalumab (anti-PD-L1) neoadjuvantly (n = 21) ( NCT03635164 ). The primary endpoint of the study was safety, which was met. Secondary endpoints included radiographic, pathologic and objective response; locoregional control; progression-free survival; and overall survival. Among evaluable patients at an early median follow-up of 16 months (448 d or 64 weeks), overall survival was 80.1% with 95% confidence interval (95% CI) (62.0%, 100.0%), locoregional control and progression-free survival were 75.8% with 95% CI (57.5%, 99.8%), and major pathological response or complete response was 75% with 95% exact CI (51.6%, 100.0%). For patients treated with 24 Gy, 89% with 95% CI (57.1%, 100.0%) had MPR or CR. Using high-dimensional multi-omics and spatial data as well as biological correlatives, we show that responders had: (1) an increase in effector T cells; (2) a decrease in immunosuppressive cells; and (3) an increase in antigen presentation post-treatment.
Assuntos
Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Radiocirurgia , Humanos , Neoplasias de Cabeça e Pescoço/terapia , Terapia Neoadjuvante/efeitos adversos , Infecções por Papillomavirus/complicações , Radiocirurgia/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapiaRESUMO
OBJECTIVE: National pathology guidelines recommend full pathologic analysis for all adult tonsillectomy specimens. We evaluated the available data on occult malignancy in adult tonsillectomy for benign indication, and created a screening system to reduce the risk of missed malignancies if routine histopathologic examination were to be discontinued. STUDY DESIGN: Retrospective chart review and systematic review of the literature. SETTING: Tertiary care academic hospital and multi-hospital private healthcare system. SUBJECTS AND METHODS: A systematic literature review identified case series of adult tonsillectomy. Retrospective chart review at our institutions from 2000 to 2016 produced an additional case series. The pooled rate of occult malignancy was determined, and re-analyzed using criteria based on preoperative risk factors designed to identify patients requiring full pathologic analysis. The predicted effects of prospective application of the proposed criteria were calculated. Pooled occult malignancy prevalence was estimated. RESULTS: Literature review and our own case series yielded 12,094 total cases. Occult malignancy prevalence in the combined data was 0.033%, representing four occult malignancies. Three out of the four would have been selected for full pathology preoperatively with use of the proposed criteria. Statistical analysis indicates that the predicted frequency of occult malignancy incidence in cases negative for the criteria is 0.01%, or 1/10,000. CONCLUSION: Application of the proposed criteria to adults undergoing tonsillectomy for benign indication identifies a subset of patients with an estimated incidence of occult malignancy similar to that reported for pediatric tonsillectomy, and potentially may permit safe elimination of pathologic analysis of their tonsil specimens. LEVEL OF EVIDENCE: Pooled analysis of case series from the literature and a single institution, level 4.
Assuntos
Biópsia/métodos , Neoplasias Primárias Desconhecidas , Tonsila Palatina , Neoplasias Tonsilares , Tonsilectomia , Adulto , Humanos , Incidência , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/epidemiologia , Neoplasias Primárias Desconhecidas/patologia , Tonsila Palatina/patologia , Tonsila Palatina/cirurgia , Neoplasias Tonsilares/diagnóstico , Neoplasias Tonsilares/epidemiologia , Neoplasias Tonsilares/patologia , Tonsilectomia/métodos , Tonsilectomia/estatística & dados numéricos , Tonsilite/cirurgia , Procedimentos Desnecessários/métodosAssuntos
Dor Abdominal/etiologia , Doença Celíaca/complicações , Síndrome de Down/complicações , Pancreatite/etiologia , Dor Abdominal/diagnóstico , Dor Abdominal/prevenção & controle , Doença Aguda , Adulto , Biópsia , Doença Celíaca/diagnóstico , Doença Celíaca/dietoterapia , Diagnóstico Diferencial , Dieta Livre de Glúten , Duodenoscopia , Feminino , Humanos , Pancreatite/diagnóstico , Pancreatite/prevenção & controle , Cooperação do Paciente , Valor Preditivo dos Testes , Recidiva , Resultado do TratamentoAssuntos
Colestase/diagnóstico , Ferritinas/sangue , Hemocromatose/diagnóstico , Hepatite C/diagnóstico , Doença Aguda , Biópsia por Agulha , Análise Química do Sangue , Colestase/patologia , Diagnóstico Diferencial , Serviço Hospitalar de Emergência , Hemocromatose/terapia , Hepatite C/patologia , Humanos , Imuno-Histoquímica , Falência Hepática/diagnóstico , Falência Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Flebotomia/métodosRESUMO
The majority of pancreatic neuroendocrine tumors (PNETs) are sporadic while 10-15% are attributable to one of several familial cancer syndromes. Hereditary forms are more commonly associated with Multiple Endocrine Neoplasia Type I and von Hippel Lindau Syndrome. However, patients with Tuberous sclerosis complex also have an increased incidence of PNETs. More often this has been reported in patients with TSC2 variants. In this case report, we summarize the literature regarding PNETs associated with Tuberous sclerosis complex, as well as present a case of a patient with a TSC1 variant and a PNET. This case highlights the association of TSC1 gene variants with these tumors and emphasizes the importance of considering such diagnoses in this patient population.
Assuntos
Angiomiolipoma/genética , Neoplasias Intestinais/genética , Neoplasias Renais/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Neoplasias Gástricas/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Esclerose Tuberosa/genética , Adulto , Angiomiolipoma/diagnóstico por imagem , Angiomiolipoma/patologia , Angiomiolipoma/cirurgia , Feminino , Mutação em Linhagem Germinativa , Humanos , Neoplasias Intestinais/diagnóstico por imagem , Neoplasias Intestinais/patologia , Neoplasias Intestinais/cirurgia , Rim/diagnóstico por imagem , Rim/patologia , Rim/cirurgia , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Pâncreas/cirurgia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Tomografia Computadorizada por Raios X , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/patologia , Esclerose Tuberosa/cirurgiaRESUMO
Background and Aims: The role of programmed cell death protein 1 (PD-1) and its ligands in the dysregulation of T helper immune responses observed in the inflammatory bowel disease (IBD) is unclear. Recently, a novel concept emerged that CD90+ colonic (myo)fibroblasts (CMFs), also known as stromal cells, act as immunosuppressors, and are among the key regulators of acute and chronic inflammation. The objective of this study was to determine if the level of the PD-1 ligands is changed in the IBD inflamed colonic mucosa and to test the hypothesis that changes in IBD-CMF-mediated PD-1 ligand-linked immunosuppression is a mechanism promoting the dysregulation of Th1 cell responses. Methods: Tissues and cells derived from Crohn's disease (CD), ulcerative colitis (UC), and healthy individuals (N) were studied in situ, ex vivo, and in culture. Results: A significant increase in programmed death-ligand 1 (PD-L1) was observed in the inflamed UC colonic mucosa when compared to the non-inflamed matched tissue samples, CD, and healthy controls. UC-CMFs were among the major populations in the colonic mucosa contributing to the enhanced PD-L1 expression. In contrast, PD-L1 expression was decreased in CD-CMFs. When compared to CD-CMFs and N-CMFs, UC-CMFs demonstrated stronger suppression of IL-2, Th1 transcriptional factor Tbet, and IFN-γ expression by CD3/CD28-activated CD4+ T cells, and this process was PD-L1 dependent. Similar observations were made when differentiated Th1 cells were cocultured with UC-CMFs. In contrast, CD-CMFs showed reduced capacity to suppress Th1 cell activity and addition of recombinant PD-L1 Fc to CD-CMF:T cell cocultures partially restored the suppression of the Th1 type responses. Conclusion: We present evidence showing that increased PD-L1 expression suppresses Th1 cell activity in UC. In contrast, loss of PD-L1 expression observed in CD contributes to the persistence of the Th1 inflammatory milieu in CD. Our data suggest that dysregulation of the Th1 responses in the inflamed colonic mucosa of IBD patients is promoted by the alterations in PD-L1 expression in the mucosal mesenchymal stromal cell compartment.
Assuntos
Antígeno B7-H1/genética , Colite Ulcerativa/etiologia , Colite Ulcerativa/metabolismo , Doença de Crohn/etiologia , Doença de Crohn/metabolismo , Células Estromais/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Antígenos Thy-1/metabolismo , Actinas/metabolismo , Adolescente , Adulto , Animais , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Colite Ulcerativa/patologia , Colite Ulcerativa/terapia , Doença de Crohn/patologia , Doença de Crohn/terapia , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Microscopia Confocal , Pessoa de Meia-Idade , Miofibroblastos/metabolismo , RNA Mensageiro/genética , Adulto JovemRESUMO
Dilated cardiomyopathy (DCM) is associated with extensive pathological cardiac remodeling and involves numerous changes in the protein expression profile of the extracellular matrix of the heart. We obtained seven human, end-stage, failing hearts with DCM (DCM-failing) and nine human, nonfailing donor hearts and compared their extracellular matrix protein profiles. We first showed that the DCM-failing hearts had indeed undergone extensive remodeling of the left ventricle myocardium relative to nonfailing hearts. We then isolated the extracellular matrix from a subset of these hearts and performed a proteomic analysis on the isolated matrices. We found that the levels of 26 structural proteins were altered in the DCM-failing isolated cardiac extracellular matrix compared to nonfailing isolated cardiac extracellular matrix. Overall, most of the extracellular matrix proteins showed reduced levels in the DCM-failing hearts, while all of the contractile proteins showed increased levels. There was a mixture of increased and decreased levels of cytoskeletal and nuclear transport proteins. Using immunoprobing, we verified that collagen IV (α2 and α6 isoforms), zyxin, and myomesin protein levels were reduced in the DCM-failing hearts. We expect that these data will add to the understanding of the pathology associated with heart failure with DCM.
Assuntos
Cardiomiopatia Dilatada/metabolismo , Matriz Extracelular/metabolismo , Adulto , Idoso , Remodelamento Atrial , Cardiomiopatia Dilatada/patologia , Cromatografia Líquida , Feminino , Imunofluorescência , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Immunoblotting , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , ProteômicaRESUMO
Granulocyte colony-stimulating factor (G-CSF) is a cytokine that is highly expressed in human and mouse colorectal cancers (CRC). We previously reported that G-CSF stimulated human CRC cell growth and migration, therefore in this study we sought to examine the therapeutic potential of anti-G-CSF treatment for CRC. G-CSF is known to mobilize neutrophils, however its impact on other immune cells has not been well examined. Here, we investigated the effects of therapeutic anti-G-CSF treatment on CRC growth and anti-tumor immune responses. C57BL/6 mice treated with azoxymethane/dextran sodium sulfate (AOM/DSS) to induce neoplasms were administered anti-G-CSF or isotype control antibodies three times a week for three weeks. Animals treated with anti-G-CSF antibodies had a marked decrease in neoplasm number and size compared to the isotype control group. Colon neutrophil and macrophage frequency were unchanged, but the number of macrophages producing IL-10 were decreased while IL-12 producing macrophages were increased. NK cells were substantially increased in colons of anti-G-CSF treated mice, along with IFNγ producing CD4(+) and CD8(+) T cells. These studies are the first to indicate a crucial role for G-CSF inhibition in promoting protective anti-tumor immunity, and suggest that anti-G-CSF treatment is a potential therapeutic approach for CRC.