RESUMO
PURPOSE: Under the continuous stimulation of tumor antigen in the tumor microenvironment, CD8+T cells will enter a state of functional defect or failure, which cannot effectively prevent the progression of lung cancer. Therefore, finding potential targets for immunotherapy in lung cancer has broad prospects. METHODS: In the early stage of this study, the genes related to immune infiltration in lung cancer were found through the analysis on multiple datasets (GSE116959, GSE139032 and GSE111894). Characteristics of candidate genes were identified from transcriptome, methylation, single cell sequencing and other dimensions, respectively. Moreover, the correlation between candidate genes and immunotherapy-related genes and mutated genes of lung cancer was further identified. Finally, the expression of the candidate genes was detected with an online immunohistochemistry database. RESULTS: According to the above research, it was found that CCL4 (chemokine (C-C motif) ligand 4) was abnormally highly expressed in samples from patients with NSCLC and had certain methylation characteristics. In addition, CCL4 was also closely associated with infiltration of immune cells, such as B cells and CD8+T cells. Interestingly, the aberrant expression of CCL4 affected the survival of CD8+T cells. Single cell sequencing results also showed that CCL4 was highly expressed in CD8+T cells and was involved in biological functions such as generation cycle. Finally, CCL4 expression was positively associated with PD-1 and PD-L1, and also with mutant genes, such as EGFR, ALK and ROS1, associated with the treatment for lung cancer. CONCLUSION: CCL4 may be a potential target for immunotherapy in patients with NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Quimiocina CCL4 , Neoplasias Pulmonares , Antígenos de Neoplasias , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimiocina CCL4/genética , Receptores ErbB/genética , Humanos , Ligantes , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/metabolismo , Mutação , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Microambiente TumoralRESUMO
Mycobacterium tuberculosis (M. tb) is the etiological agent of pulmonary tuberculosis (TB); this disease remains a worldwide health problem. Yin-Yang-1 (YY1) plays a major role in the maintenance and progression of some pulmonary diseases, including pulmonary fibrosis. However, the role of YY1 in TB remains unknown. The aim of this study was to elucidate the role of YY1 in the regulation of CCL4 and its implication in TB. We determined whether YY1 regulates CCL4 using reporter plasmids, ChIP and siRNA assays. Immunohistochemistry and digital pathology were used to measure the expression of YY1 and CCL4 in a mouse model of TB. A retrospective comparison of patients with TB and control subjects was used to measure the expression of YY1 and CCL4 using tissue microarrays. Our results showed that YY1 regulates the transcription of CCL4; moreover, YY1, CCL4 and TGF-ß were overexpressed in the lung tissues of mice with TB during the late stages of the disease and the tissues of TB patients. The expression of CCL4 and TGF-ß correlated with YY1 expression. In conclusion, YY1 regulates CCL4 transcription; moreover, YY1 is overexpressed in experimental and human TB and is positively correlated with CCL4 and TGF-ß expression. Therefore, treatments that decrease YY1 expression may be a new therapeutic strategy against TB.
Assuntos
Quimiocina CCL4/metabolismo , Pulmão/microbiologia , Tuberculose Pulmonar/metabolismo , Fator de Transcrição YY1/metabolismo , Animais , Linhagem Celular , Quimiocina CCL4/genética , Imunoprecipitação da Cromatina , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Imuno-Histoquímica , Pulmão/imunologia , Masculino , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Interferência de RNA , Estudos Retrospectivos , Transdução de Sinais , Fatores de Tempo , Análise Serial de Tecidos , Transcrição Gênica , Transfecção , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Fator de Transcrição YY1/genéticaRESUMO
The complex interplay between cytokines and chemokines regulates innate and adaptive immune responses against pathogens; specifically, cytokine and chemokine expression drives activation of immune effector cells and their recruitment to tissue infection sites. Herein, we inoculated dogs with Leishmania braziliensis antigens plus saponin (the LBSap vaccine), as well as with the vaccine components, and then used real-time PCR to evaluate the kinetics of dermal expression of mRNAs of cytokines (IL-12, IFN-γ, TNF-α, IL-4, IL-13, TGF-ß and IL-10) and chemokines (CCL2, CCL4, CCL5, CCL21 and CXCL8) 1, 12, 24 and 48 h after inoculation. We also evaluated the correlation between cytokine and chemokine expression and dermal cellularity. The LBSap vaccine induced high levels of IL-12 and IL-10 expression at 12 and 24 h, respectively. Furthermore, we observed positive correlations between IL-12 and IL-13 expression, IFN-γ and IL-13 expression, and IL-13 and TGF-ß expression, suggesting that a mixed cytokine microenvironment developed after immunization with the vaccine. Inoculation with the saponin adjuvant alone induced a chemokine and cytokine expression profile similar to that observed in the LBSap group. CCL4 and CXCL8 chemokine expression was up regulated by the LBSap vaccine. CCL5 expression was initially highest in the LBSap group, but at 48 h, expression was highest in the LB group. Information about the kinetics of the immune response to this vaccine gained using this dog model will help to elucidate the mechanisms of and factors involved in a protective response against Leishmania infection and will aid in establishing rational approaches for the development of vaccines against canine visceral leishmaniasis.