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1.
Medicine (Baltimore) ; 101(45): e31195, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36397411

RESUMO

WTAP and N6-methyladenosine (m6A) reader proteins (YTHDF2) are N6-methyladenosine (m6A) methyltransferase and m6A reading proteins, respectively. In recent years, the tumor immune environment has received more and more attention in the progress and treatment of cancer. The aim of this study was to investigate the relationship between N6-methyladenosine (m6A) methyltransferase (WTAP)/YTHDF2 and the immunological characteristics of lung adenocarcinoma (LUAD). Based on the expression of WTAP and YTHDF2 in the cancer genome atlas (TCGA) and gene expression omnibus (GEO) database, LUAD patients were divided into 2 clusters by coherently clustering method, and performed gene set enrichment analysis (GSEA) to identify the functional differences. Immunoinvasion analysis was performed using ESTIMATE, CIBERSORT, and single-sample GSEA (ssGSEA), and expression of immune checkpoint inhibitors (ICIs) targets was assessed, while tumor mutation burden (TMB) was calculated in tumor samples. Weighted gene co-expression network analysis (WGCNA) was used to identify the genes related to both WTAP/YTHDF2 expression and immunity. The immunological characteristics between the 2 clusters were externally verified based on GSE39582. The expression of WTAP was higher in cluster 1 and YTHDF2 was lower, but it was opposite in cluster 2. Cluster 1 had stronger immune infiltration, more ICIs target expression, more TMB. In addition, WGCNA identified 22 genes associated with WTAP/YTHDF2 expression and immune score, including TIM3 (HAVCR2) and CD86. WTAP and YTHDF2 influence immune contexture and may be novel prognostic and druggable targets associated with the immune system of LUAD.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Proteínas de Ligação a RNA , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenosina/metabolismo , Proteínas de Ciclo Celular/metabolismo , Metiltransferases/genética , Fatores de Processamento de RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia
2.
Cells ; 11(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36359834

RESUMO

The malignancy with the greatest global mortality rate is lung cancer. Lung adenocarcinoma (LUAD) is the most common subtype. The evidence demonstrated that voltage-gated potassium channel subunit beta-2 (KCNAB2) significantly participated in the initiation of colorectal cancer and its progression. However, the biological function of KCNAB2 in LUAD and its effect on the tumor immune microenvironment are still unknown. In this study, we found that the expression of KCNAB2 in tissues of patients with LUAD was markedly downregulated, and its downregulation was linked to accelerated cancer growth and poor clinical outcomes. In addition, low KCNAB2 expression was correlated with a deficiency in immune infiltration. The mechanism behind this issue might be that KCNAB2 influenced the immunological process such that the directed migration of immune cells was affected. Furthermore, overexpression of KCNAB2 in cell lines promoted the expression of CCL2, CCL3, CCL4, CCL18, CXCL9, CXCL10, and CXCL12, which are necessary for the recruitment of immune cells. In conclusion, KCNAB2 may play a key function in immune infiltration and can be exploited as a predictive biomarker for evaluating prognosis and a possible immunotherapeutic target.


Assuntos
Adenocarcinoma de Pulmão , Superfamília Shaker de Canais de Potássio , Humanos , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Superfamília Shaker de Canais de Potássio/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Prognóstico
3.
Arch. Soc. Esp. Oftalmol ; 97(11): 655-658, nov. 2022. ilus
Artigo em Espanhol | IBECS | ID: ibc-212047

RESUMO

Se presenta el caso de retinopatía autoinmune en un paciente con carcinoma microcítico de pulmón, no conocido hasta el momento, que se diagnosticó tras la exploración oftalmológica. La serología fue positiva para anticuerpos onconeuronales CV2/CRMP5. La retinopatía autoinmune es una entidad rara que puede pasarse por alto, y ser infradiagnosticada. Se produce por una reacción inmunomediada contra antígenos retinianos. La importancia de su diagnóstico precoz radica en que en muchos de los pacientes la sintomatología ocular aparece antes del diagnóstico del cáncer primario, por lo que su identificación y derivación precoz para estudio de extensión puede suponer el diagnóstico de una neoplasia primaria oculta hasta el momento. (AU)


We present a case of autoimmune retinopathy in a patient with unknown small cell lung cáncer (SCLC), which was diagnosed after ophthalmological examination. Serology was positive for CV2/CRMP5 onconeuronal antibodies. Autoimmune retinopathy is a rare entity that can be missed and underdiagnosed. It is produced by an immune-mediated reaction against retinal antigens. The importance of its early diagnosis lies in the fact that in many of the patients, ocular symptoms appear before the diagnosis of the primary cancer, so its early identification and referral for an extension study may lead to the diagnosis of a hidden primary neoplasm. (AU)


Assuntos
Humanos , Masculino , Idoso , Doenças Retinianas/imunologia , Autoanticorpos/imunologia , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/imunologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Detecção Precoce de Câncer , Angiofluoresceinografia
4.
Cells ; 11(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36291098

RESUMO

BACKGROUND: Lung cancer (LC) tissue for immunological characterization is often scarce. We explored and compared T cell characteristics between broncho-alveolar lavage from tumor affected (t-BAL) and contralateral lung (cl-BAL), with matched peripheral blood (PB). METHODS: BAL and PB were collected during bronchoscopy for diagnostic and/or therapeutic purposes in patients with monolateral primary lesion. RESULTS: Of 33 patients undergoing BAL and PB sampling, 21 had histologically-confirmed LC. Most cases were locally-advanced or metastatic non-small cell LC. T cell characteristics were not significantly different in t-BAL vs. cl-BAL. Compared to PB, CD8 T cells in BAL presented features of immune activation and exhaustion (high PD-1, low IFN-g production). Accordingly, regulatory CD4 T cells were also higher in BAL vs. PB. When dichotomizing T cell density in t-BAL in high and low, we found that PD-L1 expression in LC was associated with T cell density in t-BAL. T-BAL with high T cell density had higher %IFN-g+CD8 T cells and lower %T-regs. CONCLUSION: In BAL from advanced LC patients, T cells present features of exhaustion. T cells in t-BAL could be the best surrogate of tumor-infiltrating T cell, and future studies should evaluate T cell phenotype and density as potential biomarkers for cancer immunotherapy outcome.


Assuntos
Neoplasias Pulmonares , Subpopulações de Linfócitos T , Humanos , Antígeno B7-H1/metabolismo , Líquido da Lavagem Broncoalveolar , Interferon gama/metabolismo , Neoplasias Pulmonares/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Subpopulações de Linfócitos T/imunologia
5.
J Immunother Cancer ; 10(10)2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36192086

RESUMO

BACKGROUND: Current immunotherapies still have limited successful rates among cancers. It is now recognized that T cell functional state in the tumor microenvironment (TME) is a key determinant for effective antitumor immunity and immunotherapy. In addition to exhaustion, cellular senescence in tumor-infiltrating T cells (TILs) has recently been identified as an important T cell dysfunctional state induced by various malignant tumors. Therefore, a better understanding of the molecular mechanism responsible for T cell senescence in the TME and development of novel strategies to prevent effector T cell senescence are urgently needed for cancer immunotherapy. METHODS: Senescent T cell populations in the TMEs in mouse lung cancer, breast cancer, and melanoma tumor models were evaluated. Furthermore, T cell senescence induced by mouse tumor and regulatory T (Treg) cells in vitro was determined with multiple markers and assays, including real-time PCR, flow cytometry, and histochemistry staining. Loss-of-function strategies with pharmacological inhibitors and the knockout mouse model were used to identify the potential molecules and pathways involved in T cell senescence. In addition, melanoma mouse tumor immunotherapy models were performed to explore the synergistical efficacy of antitumor immunity via prevention of tumor-specific T cell senescence combined with anti-programmed death-ligand 1 (anti-PD-L1) checkpoint blockade therapy. RESULTS: We report that both mouse malignant tumor cells and Treg cells can induce responder T cell senescence, similar as shown in human Treg and tumor cells. Accumulated senescent T cells also exist in the TME in tumor models of lung cancer, breast cancer and melanoma. Induction of ataxia-telangiectasia mutated protein (ATM)-associated DNA damage is the cause for T cell senescence induced by both mouse tumor cells and Treg cells, which is also regulated by mitogen-activated protein kinase (MAPK) signaling. Furthermore, blockages of ATM-associated DNA damage and/or MAPK signaling pathways in T cells can prevent T cell senescence mediated by tumor cells and Treg cells in vitro and enhance antitumor immunity and immunotherapy in vivo in adoptive transfer T cell therapy melanoma models. Importantly, prevention of tumor-specific T cell senescence via ATM and/or MAPK signaling inhibition combined with anti-PD-L1 checkpoint blockade can synergistically enhance antitumor immunity and immunotherapy in vivo. CONCLUSIONS: These studies prove the novel concept that targeting both effector T cell senescence and exhaustion is an effective strategy and can synergistically enhance cancer immunotherapy.


Assuntos
Neoplasias da Mama , Imunoterapia , Neoplasias Pulmonares , Melanoma , Linfócitos T , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Senescência Celular , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Melanoma/imunologia , Melanoma/terapia , Camundongos , Proteínas Quinases Ativadas por Mitógeno , Linfócitos T/citologia , Microambiente Tumoral
6.
Clin Cancer Res ; 28(22): 4835-4837, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36103258

RESUMO

SUMMARY: Analysis of tumor-infiltrating lymphocyte (TIL) functional states, particularly tumor-reactive PD-1T TILs, within specific spatial context, can serve as a biologically informed predictive marker of immunotherapy that may be superior to standard clinical biomarkers. High-plex quantitative immune cell phenotyping within their spatial context has tremendous potential in immuno-oncology. See related article by Hummelink et al., p. 4893.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Antígeno B7-H1/imunologia , Receptor de Morte Celular Programada 1 , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pulmonares/imunologia
7.
World J Surg Oncol ; 20(1): 275, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36050740

RESUMO

BACKGROUND: Lung adenocarcinoma (LUAD) accounts for 50% of lung cancers, with high mortality and poor prognosis. Long non-coding RNA (lncRNA) plays a vital role in the progression of tumors. Cuproptosis is a newly discovered form of cell death that is highly investigated. Therefore, in the present study, we aimed to investigate the role of cuproptosis-related lncRNA signature in clinical prognosis prediction and immunotherapy and the relationship with drug sensitivity. MATERIAL AND METHODS: Genomic and clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and cuproptosis-related genes were obtained from cuproptosis-related studies. The prognostic signature was constructed by co-expression analysis and Cox regression analysis. Patients were divided into high and low risk groups, and then, a further series of model validations were carried out to assess the prognostic value of the signature. Subsequently, lncRNAs were analyzed for gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes Enrichment (KEGG), immune-related functions, and tumor mutation burden (TMB). Finally, we used tumor immune dysfunction and exclusion (TIDE) algorithms on immune escape and immunotherapy of cuproptosis-related lncRNAs, thereby identifying its sensitivity toward potential drugs for LUAD. RESULTS: A total of 16 cuproptosis-related lncRNAs were obtained, and a prognostic signature was developed. We found that high-risk patients had worse overall survival (OS) and progression-free survival (PFS) and higher mortality. Independent prognostic analyses, ROC, C-index, and nomogram showed that the cuproptosis-related lncRNAs can accurately predict the prognosis of patients. The nomogram and heatmap showed a distinct distribution of the high- and low-risk cuproptosis-related lncRNAs. Enrichment analysis showed that the biological functions of lncRNAs are associated with tumor development. We also found that immune-related functions, such as antiviral activity, were suppressed in high-risk patients who had mutations in oncogenes. OS was poorer in patients with high TMB. TIDE algorithms showed that high-risk patients have a greater potential for immune escape and less effective immunotherapy. CONCLUSION: To conclude, the 16 cuproptosis-related lncRNAs can accurately predict the prognosis of patients with LUAD and may provide new insights into clinical applications and immunotherapy.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , RNA Longo não Codificante , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Humanos , Imunidade , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
8.
J Immunother Cancer ; 10(7)2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35793868

RESUMO

BACKGROUND: Understanding the mechanisms of non-T cell inflamed tumor microenvironment (TME) and their modulation are important to improve cancer immunotherapies such as immune checkpoint inhibitors. The involvement of various immunometabolisms has recently been indicated in the formation of immunosuppressive TME. In this study, we investigated the immunological roles of stearoyl-CoA desaturase 1 (SCD1), which is essential for fatty acid metabolism, in the cancer immune response. METHODS: We investigated the roles of SCD1 by inhibition with the chemical inhibitor or genetic manipulation in antitumor T cell responses and the therapeutic effect of anti-programmed cell death protein 1 (anti-PD-1) antibody using various mouse tumor models, and their cellular and molecular mechanisms. The roles of SCD1 in human cancers were also investigated by gene expression analyses of colon cancer tissues and by evaluating the related free fatty acids in sera obtained from patients with non-small cell lung cancer who were treated with anti-PD-1 antibody. RESULTS: Systemic administration of a SCD1 inhibitor in mouse tumor models enhanced production of CCL4 by cancer cells through reduction of Wnt/ß-catenin signaling and by CD8+ effector T cells through reduction of endoplasmic reticulum stress. It in turn promoted recruitment of dendritic cells (DCs) into the tumors and enhanced the subsequent induction and tumor accumulation of antitumor CD8+ T cells. SCD1 inhibitor was also found to directly stimulate DCs and CD8+ T cells. Administration of SCD1 inhibitor or SCD1 knockout in mice synergized with an anti-PD-1 antibody for its antitumor effects in mouse tumor models. High SCD1 expression was observed in one of the non-T cell-inflamed subtypes in human colon cancer, and serum SCD1 related fatty acids were correlated with response rates and prognosis of patients with non-small lung cancer following anti-PD-1 antibody treatment. CONCLUSIONS: SCD1 expressed in cancer cells and immune cells causes immunoresistant conditions, and its inhibition augments antitumor T cells and therapeutic effects of anti-PD-1 antibody. Therefore, SCD1 is an attractive target for the development of new diagnostic and therapeutic strategies to improve current cancer immunotherapies including immune checkpoint inhibitors.


Assuntos
Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias do Colo , Neoplasias Pulmonares , Estearoil-CoA Dessaturase , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Camundongos , Camundongos Knockout , Estearoil-CoA Dessaturase/antagonistas & inibidores , Estearoil-CoA Dessaturase/imunologia , Microambiente Tumoral , Via de Sinalização Wnt/imunologia , beta Catenina/imunologia
9.
BMC Cancer ; 22(1): 738, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794593

RESUMO

BACKGROUND: Immune checkpoint blockade (ICB) only works well for a certain subset of patients with non-small cell lung cancer (NSCLC). Therefore, biomarkers for patient stratification are desired, which can suggest the most beneficial treatment. METHODS: In this study, three datasets (GSE126044, GSE135222, and GSE136961) of immunotherapy from the Gene Expression Omnibus (GEO) database were analyzed, and seven intersected candidates were extracted as potential biomarkers for ICB followed by validation with The Cancer Genome Atlas (TCGA) dataset and the in-house cohort data. RESULTS: Among these candidates, we found that human leukocyte antigen-DR alpha (HLA-DRA) was downregulated in NSCLC tissues and both tumor and immune cells expressed HLA-DRA. In addition, HLA-DRA was associated with an inflamed tumor microenvironment (TME) and could predict the response to ICB in NSCLC. Moreover, we validated the predictive value of HLA-DRA in immunotherapy using an in-house cohort. Furthermore, HLA-DRA was related to the features of inflamed TME in not only NSCLC but also in most cancer types. CONCLUSION: Overall, HLA-DRA could be a promising biomarker for guiding ICB in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Cadeias alfa de HLA-DR , Neoplasias Pulmonares , Receptor de Morte Celular Programada 1 , Biomarcadores Tumorais/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Cadeias alfa de HLA-DR/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Fatores Imunológicos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Valor Preditivo dos Testes , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral
10.
Cancer Immunol Res ; 10(9): 1111-1126, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35802887

RESUMO

Epidermal growth factor receptor (EGFR) is the most frequently mutated driver oncogene in nonsmoking-related, non-small cell lung cancer (NSCLC). EGFR-mutant NSCLC has a noninflamed tumor microenvironment (TME), with low infiltration by CD8+ T cells and, thus, immune-checkpoint inhibitors, such as antiprogrammed cell death-1 (anti-PD-1), have weak antitumor effects. Here, we showed that CD8+ T-cell responses were induced by an EGFR-tyrosine kinase inhibitor (TKI) in syngeneic Egfr-mutant NSCLC tumors, which was further pronounced by the sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2). However, the simultaneous triple blockade had no such effect. The PD-1/VEGFR2 dual blockade did not exert tumor-inhibitory effects without pretreatment with the EGFR-TKI, suggesting that the treatment schedule is crucial for the efficacy of the dual blockade therapy. Pretreatment with EGFR-TKI increased the CD8+ T-cell/regulatory T-cell (Treg) ratio, while also increasing the expression of immunosuppressive chemokines and chemokine receptors, as well as increasing the number of M2-like macrophages, in the TME. Discontinuing EGFR-TKI treatment reversed the transient increase of immunosuppressive factors in the TME. The subsequent PD-1/VEGFR2 inhibition maintained increased numbers of infiltrating CD8+ T cells and CD11c+ dendritic cells. Depletion of CD8+ T cells in vivo abolished tumor growth inhibition by EGFR-TKI alone and the sequential triple therapy, suggesting that EGFR inhibition is a prerequisite for the induction of CD8+ T-cell responses. Our findings could aid in developing an alternative immunotherapy strategy in patients with cancers that have driver mutations and a noninflamed TME.


Assuntos
Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Receptores ErbB , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Microambiente Tumoral , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
11.
Front Immunol ; 13: 877896, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720373

RESUMO

The six transcriptomic immune subtypes (ISs) (C1 - C6) were reported to have complex and different interplay between TME and cancer cells in TCGA (The Cancer Genome Atlas) pan-cancer cohort. Our study specifically explored how the consequence of interplay determines the prognosis and the response to therapy in LUAD cohorts. Clinical and molecular information of LUAD patients were from TCGA and Gene Expression Omnibus (GEO). The immune cell populations and gene/pathway enrichment analysis were performed to explore the molecular differences among the C3 IS and other ISs in the LUAD population. The proportion of C3 inflammatory IS was identified as the most common IS in both TCGA (N = 457) and GEO (N = 901) cohorts. The C3 IS was also found to be the most accurate prognostic subtype, which was associated with significantly longer OS (p <0.001) and DFS (p <0.001). The C3 IS presented higher levels of CD8 T, M1 macrophage, and myeloid dendritic cells, while lower levels of M2 macrophages and cancer-associated fibroblast cells. Moreover, the C3 subtype was enriched in the antigen process and presenting, interferon-gamma response, T cell receptor signaling, and natural killer cell-mediated cytotoxicity pathways than C1/C2. In contrast, the C1/C2 presented greater activation of pathways related to the cell cycles, DNA repair, and p53 signaling pathways. The immune-related C3 IS had a great ability to stratify the prognosis of LUAD, providing clues for further pathogenic research. This classification might help direct precision medicine screenings of LUAD patients, thus possibly improving their prognoses.


Assuntos
Adenocarcinoma de Pulmão , Macrófagos , Microambiente Tumoral , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/terapia , Humanos , Interferon gama/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Macrófagos/imunologia , Prognóstico , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia
12.
Nature ; 607(7917): 149-155, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35705813

RESUMO

Immunosurveillance of cancer requires the presentation of peptide antigens on major histocompatibility complex class I (MHC-I) molecules1-5. Current approaches to profiling of MHC-I-associated peptides, collectively known as the immunopeptidome, are limited to in vitro investigation or bulk tumour lysates, which limits our understanding of cancer-specific patterns of antigen presentation in vivo6. To overcome these limitations, we engineered an inducible affinity tag into the mouse MHC-I gene (H2-K1) and targeted this allele to the KrasLSL-G12D/+Trp53fl/fl mouse model (KP/KbStrep)7. This approach enabled us to precisely isolate MHC-I peptides from autochthonous pancreatic ductal adenocarcinoma and from lung adenocarcinoma (LUAD) in vivo. In addition, we profiled the LUAD immunopeptidome from the alveolar type 2 cell of origin up to late-stage disease. Differential peptide presentation in LUAD was not predictable by mRNA expression or translation efficiency and is probably driven by post-translational mechanisms. Vaccination with peptides presented by LUAD in vivo induced CD8+ T cell responses in naive mice and tumour-bearing mice. Many peptides specific to LUAD, including immunogenic peptides, exhibited minimal expression of the cognate mRNA, which prompts the reconsideration of antigen prediction pipelines that triage peptides according to transcript abundance8. Beyond cancer, the KbStrep allele is compatible with other Cre-driver lines to explore antigen presentation in vivo in the pursuit of understanding basic immunology, infectious disease and autoimmunity.


Assuntos
Antígenos de Neoplasias , Peptídeos , Proteômica , Células Epiteliais Alveolares/imunologia , Animais , Apresentação de Antígeno , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/química , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Neoplasias Pulmonares/química , Neoplasias Pulmonares/imunologia , Camundongos , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/imunologia , Peptídeos/análise , Peptídeos/química , Peptídeos/imunologia , RNA Mensageiro
13.
BMC Cancer ; 22(1): 632, 2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35676688

RESUMO

BACKGROUND: Semaphorins have been found to play important roles in multiple malignancy-related processes. However, the role of Semaphorin 4B (SEMA4B) in lung cancer remains unclear. Here, we aimed to explore the biological functions of SEMA4B in through bioinformatic analysis, in vitro and in vivo assays. In the present study, the possible mechanism by which SEMA4B affected the tumor growth and microenvironment of lung adenocarcinoma (LUAD) were investigated. METHODS: The expression of SEMA4B in LUAD was analyzed by bioinformatic analysis and verified by the immunohistochemistry staining. The prognostic value of SEMA4B in LUAD was investigated using the Kaplan-Meier survival and Cox's regression model. After silencing SEMA4B expression, the functions of SEMA4B in LUAD cells were investigated by in vitro experiments, including CCK-8 and plate clone formation. And the effect of SEMA4B on tumor growth and immune infiltration was explored in C57BL/6 mice tumor-bearing models. RESULTS: SEMA4B expression was upregulated in LUAD tissues and correlated with later pathological stages and poor prognosis of LUAD patients. Further study found that SEMA4B silencing suppressed the proliferation of lung cancer cells both in vitro and in vivo. Bioinformatic analysis showed that SEMA4B expression was correlated with the increased infiltration of myeloid-derived suppressor cells (MDSCs), T-regs and the decreased infiltration of CD8+ T cell in LUAD. Importantly, in vivo study verified that the infiltration of T-regs and MDSCs in tumor microenvironment (TME) of Xenograft tissues was decreased after SEMA4B silencing. CONCLUSIONS: These findings demonstrated SEMA4B might play an oncogenic role in LUAD progression, and be a promising therapeutic target for lung cancer.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Semaforinas , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Animais , Proliferação de Células/genética , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Prognóstico , Semaforinas/genética , Semaforinas/metabolismo , Microambiente Tumoral
14.
J Clin Lab Anal ; 36(7): e24538, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35689561

RESUMO

BACKGROUND: Lung adenocarcinoma (LUAD) results in a majority of cancer burden worldwide. TP53 is the most commonly mutated in LUAD. This study aimed to reveal the relation between TP53 and tumor microenvironment (TME) for improving LUAD treatment. METHODS: Differentially expressed genes (DEGs) related to immunity were analyzed between TP53-WT and TP53-MUT groups. Least absolute shrinkage and selection operator (LASSO) Cox regression was applied to screen prognostic DEGs. Two independent datasets were included to evaluate the robustness of the prognostic model. RESULTS: An 8-gene prognostic model containing ANLN, CCNB1, DLGAP5, FAM83A, GJB2, NAPSA, SFTPB, and SLC2A1 was established based on DEGs. LUAD samples were classified into high- and low-risk groups with differential overall survival in the two datasets. M0 macrophages, M1 macrophages, and activated memory CD4 T cells were more enriched in high-risk group. Immune checkpoints of PDCD1, LAG3, and CD274 were also high-expressed in high-risk group. CONCLUSION: The study improved the understanding of the role of TP53 in the TME modulation. The 8-gene model had robust performance to predict LUAD prognosis in clinical practice. In addition, the eight prognostic genes may also serve as potential targets for designing therapeutic drugs for LUAD patients.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Proteína Supressora de Tumor p53 , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Proteínas de Neoplasias/genética , Prognóstico , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética
15.
Cell Rep ; 39(7): 110814, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35584676

RESUMO

Small cell lung cancers (SCLCs) have high mutational burden but are relatively unresponsive to immune checkpoint blockade (ICB). Using SCLC models, we demonstrate that inhibition of WEE1, a G2/M checkpoint regulator induced by DNA damage, activates the STING-TBK1-IRF3 pathway, which increases type I interferons (IFN-α and IFN-ß) and pro-inflammatory chemokines (CXCL10 and CCL5), facilitating an immune response via CD8+ cytotoxic T cell infiltration. We further show that WEE1 inhibition concomitantly activates the STAT1 pathway, increasing IFN-γ and PD-L1 expression. Consistent with these findings, combined WEE1 inhibition (AZD1775) and PD-L1 blockade causes remarkable tumor regression, activation of type I and II interferon pathways, and infiltration of cytotoxic T cells in multiple immunocompetent SCLC genetically engineered mouse models, including an aggressive model with stabilized MYC. Our study demonstrates cell-autonomous and immune-stimulating activity of WEE1 inhibition in SCLC models. Combined inhibition of WEE1 plus PD-L1 blockade represents a promising immunotherapeutic approach in SCLC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Proteínas de Ciclo Celular , Neoplasias Pulmonares , Proteínas de Membrana , Proteínas Tirosina Quinases , Fator de Transcrição STAT1 , Carcinoma de Pequenas Células do Pulmão , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Fator de Transcrição STAT1/metabolismo , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia
16.
Zhonghua Zhong Liu Za Zhi ; 44(5): 382-388, 2022 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-35615793

RESUMO

Objective: To investigate the role of CXCL5 in tumor immune of lung cancer and to explore the potential molecular mechanisms. Methods: A total of 62 cases of patients with lung cancer admitted in the First Affiliated Hospital of Henan University from May 2018 to December 2019 were recruited as study object. Another 20 cases of patients with pulmonary infectious diseases and 20 cases of healthy control were selected as control. Enzyme-linked immunosorbent assay (ELISA) was used to determine serum levels of CXCL5 in patients with lung cancer, pulmonary infectious diseases and healthy control. Immunohistochemical staining (IHC) was used to detect the expressions of CXCL5 and PD-1/PD-L1 in tumor and paracarcinoma tissues of patients with lung cancer. Pearson correlation analysis was used to evaluate the correlation between CXCL5 and PD-1 in tumor and paracarcinoma tissues of patients with lung cancer. Lewis cells either expressing CXCL5 or vector plasmids were used to establish C57BL/6J mice model of lung cancer, and all mice were then divided into vehicle and PD-1 antibody treatment groups, 10 mice for each group. The mice survival and tumor growth curves were recorded. IHC was used to evaluate the expressions of CXCL5, PD-1 as well as the proportions of CD8(+) T and Treg cells in xenograft tumor tissues. Results: In patients with lung cancer, the serum level of CXCL5 [(351.7±51.5) ng/L] was significant higher than that in patients with pulmonary infectious diseases and healthy control [(124.7±23.4) ng/L, P<0.001]. The expression levels of CXCL5 (0.136±0.034), CXCR2 (0.255±0.050), PD-1 (0.054±0.012) and PD-L1 (0.350±0.084) in tumor were significant higher than those in paracarcinoma normal tissues [(0.074±0.022), (0.112±0.023), (0.041±0.007) and (0.270±0.043) respectively, P<0.001]. CXCL5 was significant positively correlated with PD-1 in tumor tissues of lung cancer (r=0.643, P<0.001), but not correlated with PD-1 in paracarcinoma tissues(r=0.088, P=0.496). The vector control group, CXCL5 overexpression group, vector control + anti-PD-1 antibody treatment group and CXCL5 overexpression + anti-PD-1 antibody treatment group all successfully formed tumors in mice, while CXCL5 overexpression increased the tumor growth significantly (P<0.01), which was abrogated by the treatment of anti-PD-1 antibody. CXCL5 overexpression decreased the mice survival time significantly (P<0.01), this effect was also abrogated by the treatment of anti-PD-1 antibody. The proportion of CD8(+) T cells in CXCL5 overexpression group [(10.40±2.00)%] was significant lower than that in vector control group [(21.20±3.30)%, P=0.002]. The proportion of CD4(+) Foxp3(+) Treg cells in CXCL5 overexpression group [(38.40±3.70)%] was significant higher than that in vector control group [(23.30±2.25)%, P<0.001]. After the treatment of anti-PD-1 antibody, no significant difference were observed for the proportion of CD8(+) T cells [(34.10±5.00)% and (33.40±4.00)% respectively] and Treg cells [(14.70±3.50)% and (14.50±3.30)% respectively] in xenograft tumor tissues between CXCL5 overexpression+ anti-PD-1 antibody treatment group and vector control + anti-PD-1 antibody treatment group (P>0.05). Conclusion: The expressions of CXCL5 and PD-1/PD-L1 are all increased significantly in the tumor tissues of patients with lung cancer, CXCL5 may inhibit tumor immune of lung cancer via modulating PD-1/PD-L1 signaling.


Assuntos
Antígeno B7-H1 , Quimiocina CXCL5 , Neoplasias Pulmonares , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos , Quimiocina CXCL5/metabolismo , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/metabolismo
17.
Cancer Lett ; 539: 215712, 2022 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-35490920

RESUMO

The epithelial-to-mesenchymal transition (EMT) is involved in cancer metastasis; nevertheless, interferon (IFN)-γ induces anticancer activities by causing cell growth suppression, cytotoxicity, and migration inhibition. Regarding the poor response to exogenously administered IFN-γ as anticancer therapy, it was hypothesized that malignant cells may acquire a means of escaping from IFN-γ immunosurveillance, likely through an EMT-related process. A genomic analysis of human lung cancers revealed a negative link between the EMT and IFN-γ signaling, while compared to human lung adenocarcinoma A549 cells, IFN-γ-hyporesponsive AS2 cells exhibited mesenchymal characteristics. Chemically, physically, and genetically engineered EMT attenuated IFN-γ-induced IFN regulatory factor 1 transactivation. Poststimulation of transforming growth factor-ß induced the EMT and also selectively retarded IFN-γ-responsive gene expression as well as IFN-γ-induced signal transducer and activator of transcription 1 activation, major histocompatibility complex I, and CD54 expression, cell migration/invasion inhibition, and direct/indirect cytotoxicity. Without changes in IFN-γ receptors, excessive oxidative activation of Src homology-2 containing phosphatase 2 (SHP2) in cells undergoing the EMT primarily caused cellular hyporesponsiveness to IFN-γ signaling and cytotoxicity, while combining an SHP2 inhibitor or antioxidant sensitized EMT-associated AS2 and mesenchymal A549 cells to IFN-γ-induced priming effects on tumor necrosis factor-related apoptosis-inducing ligand cytotoxicity. In cell line-derived xenograft models, combined treatment with IFN-γ and an SHP2 inhibitor induced enhanced anticancer activities. These results imply that EMT-associated SHP2 activation inhibits IFN-γ signaling, facilitating lung cancer cell escape from IFN-γ immunosurveillance.


Assuntos
Interferon gama , Neoplasias Pulmonares , Linhagem Celular Tumoral , Movimento Celular/imunologia , Transição Epitelial-Mesenquimal/imunologia , Humanos , Vigilância Imunológica , Interferon gama/imunologia , Interferon gama/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia
18.
Cell Metab ; 34(6): 874-887.e6, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35504291

RESUMO

The tumor microenvironment (TME) contains a rich source of nutrients that sustains cell growth and facilitate tumor development. Glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert antitumor function. Immunotherapy unleashes T cell antitumor function, and although many solid tumors respond well, a significant proportion of patients do not benefit. In patients with KRAS-mutant lung adenocarcinoma, KEAP1 and STK11/Lkb1 co-mutations are associated with impaired response to immunotherapy. To investigate the metabolic and immune microenvironment of KRAS-mutant lung adenocarcinoma, we generated murine models that reflect the KEAP1 and STK11/Lkb1 mutational landscape in these patients. Here, we show increased glutamate abundance in the Lkb1-deficient TME associated with CD8 T cell activation in response to anti-PD1. Combination treatment with the glutaminase inhibitor CB-839 inhibited clonal expansion and activation of CD8 T cells. Thus, glutaminase inhibition negatively impacts CD8 T cells activated by anti-PD1 immunotherapy.


Assuntos
Quinases Proteína-Quinases Ativadas por AMP , Adenocarcinoma de Pulmão , Linfócitos T CD8-Positivos , Glutaminase , Neoplasias Pulmonares , Quinases Proteína-Quinases Ativadas por AMP/deficiência , Quinases Proteína-Quinases Ativadas por AMP/imunologia , Quinases Proteína-Quinases Ativadas por AMP/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Glutaminase/antagonistas & inibidores , Glutaminase/imunologia , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Ativação Linfocitária , Camundongos , Mutação , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Microambiente Tumoral
19.
JCI Insight ; 7(11)2022 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-35471938

RESUMO

K-ras-mutant lung adenocarcinoma (KM-LUAD) is associated with abysmal prognosis and is tightly linked to tumor-promoting inflammation. A human mAb, canakinumab, targeting the proinflammatory cytokine IL-1ß, significantly decreased the risk of lung cancer in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Interestingly, we found high levels of IL-1ß in the lungs of mice with K-rasG12D-mutant tumors (CC-LR mice). Here, we blocked IL-1ß using an anti-IL-1ß mAb in cohorts of 6- or 14-week-old CC-LR mice to explore its preventive and therapeutic effect, respectively. IL-1ß blockade significantly reduced lung tumor burden, which was associated with reprogramming of the lung microenvironment toward an antitumor phenotype characterized by increased infiltration of cytotoxic CD8+ T cells (with high IFN-γ and granzyme B expression but low programmed cell death 1 [PD-1] expression) while suppressing neutrophils and polymorphonuclear (PMN) myeloid-derived suppressor cells. When querying the Cancer Genome Atlas data set, we found positive correlations between IL1B expression and infiltration of immunosuppressive PMNs and expression of their chemoattractant, CXCL1, and PDCD1 expressions in patients with KM-LUAD. Our data provide evidence that IL-1ß blockade may be a preventive strategy for high-risk individuals and an alternative therapeutic approach in combination with currently available treatments for KM-LUAD.


Assuntos
Adenocarcinoma de Pulmão , Anticorpos Monoclonais Humanizados , Interleucina-1beta , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Citocinas/biossíntese , Citocinas/imunologia , Genes ras , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Camundongos , Terapia de Alvo Molecular , Mutação , Neutrófilos/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Microambiente Tumoral
20.
Oncoimmunology ; 11(1): 2059874, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35402080

RESUMO

Lung cancer is one of the most common causes of brain metastases and is always associated with poor prognosis. We investigated the immunophenotypes of primary lung tumors and paired brain metastases, as well as immunophenotypes in the synchronous group (patients with brain metastases upon initial diagnosis) and metachronous group (patients developed brain metastases during the course of their disease). RNA sequencing of eighty-six samples from primary lung tumors and paired brain metastases of 43 patients was conducted to analyze the tumor immune microenvironment. Our data revealed that matched brain metastases compared with primary lung tumors exhibited reduced tumor infiltrating lymphocytes (TILs), a higher fraction of neutrophils infiltration, decreased scores of immune-related signatures, and a lower proportion of tumor microenvironment immune type I (high PD-L1/high CD8A) tumors. Additionally, we found a poor correlation of PD-L1 expression between paired brain metastases and primary lung tumors. In addition, gene set enrichment analysis (GSEA) showed that some gene sets associated with the immune response were enriched in the metachronous group, while other gene sets associated with differentiation and metastasis were enriched in the synchronous group in the primary lung tumors. Moreover, the tumor immune microenvironment between paired brain metastases and primary lung tumors displayed more differences in the metachronous group than in the synchronous group. Our work illustrates that brain metastatic tumors are more immunosuppressed than primary lung tumors, which may help guide immunotherapeutic strategies for NSCLC brain metastases.


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Microambiente Tumoral , Antígeno B7-H1/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Microambiente Tumoral/imunologia
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