RESUMO
The patient was a 66-year-old male who had undergone an operation for lung cancer and solitary brain metastases. Follow- up PET-CT after 1 year detected FDG accumulation in the stomach. We performed esophagogastroscopy and found an approximately 20 mm-sized Type 2 tumor on the greater curvature of the upper stomach. A pathological diagnosis of lung adenocarcinoma metastasis in the stomach was made. Laparoscopic surgery was performed on the metastatic lesion to prevent bleeding and perforation, and resection was achieved with minimal invasion. The current development of chemotherapy, including immunotherapy, has contributed to the improved prognosis of cancer patients, including those with lung metastasis in the stomach. Considering these backgrounds, preventive surgical resection under laparoscopy may be an effective approach for improving prognosis and preventing acute life-threatening adverse events. We report this case along with a literature review.
Assuntos
Laparoscopia , Neoplasias Pulmonares , Neoplasias Gástricas , Idoso , Gastrectomia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgiaRESUMO
Despite multidisciplinary treatment for patients with advanced gastric cancer, their prognosis remains poor. Therefore, the development of novel therapeutic strategies is urgently needed, and immunotherapy utilizing anti-programmed death 1/-programmed death ligand-1 mAb is an attractive approach. However, as there is limited information on how programmed death ligand-1 is upregulated on tumor cells within the tumor microenvironment, we examined the mechanism of programmed death ligand-1 regulation with a particular focus on interferon gamma in an in vitro setting and in clinical samples. Our in vitro findings showed that interferon gamma upregulated programmed death ligand-1 expression on solid tumor cells through the JAK-signal transducer and activator of transcription pathway, and impaired the cytotoxicity of tumor antigen-specific CTL against tumor cells. Following treatment of cells with anti-programmed death ligand-1 mAb after interferon gamma-pre-treatment, the reduced anti-tumor CTL activity by interferon gamma reached a higher level than the non-treatment control targets. In contrast, programmed death ligand-1 expression on tumor cells also significantly correlated with epithelial-mesenchymal transition phenotype in a panel of solid tumor cells. In clinical gastric cancer samples, tumor membrane programmed death ligand-1 expression significantly positively correlated with the presence of CD8-positive T cells in the stroma and interferon gamma expression in the tumor. The results suggest that gastric cancer patients with high CD8-positive T-cell infiltration may be more responsive to anti-programmed death 1/-programmed death ligand-1 mAb therapy.
Assuntos
Antígeno B7-H1/metabolismo , Interferon gama/metabolismo , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/genética , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Neoplasias Gástricas/genética , Linfócitos T Citotóxicos/metabolismo , Microambiente TumoralRESUMO
BACKGROUND: We conducted a phase I/Ib, open-label, single-arm trial to assess the safety, tolerability and optimal scheduling regimen of OTSGC-A24 cancer vaccine in patients with advanced gastric cancer. METHODS: Patients with advanced gastric cancer with HLA-A*24:02 haplotype were included in this study. OTSGC-A24 was administered at 1 mg in 3-weekly (3w), 2-weekly (2w), and weekly (1w) cohorts to evaluate the safety, immunological response and schedule. Based on the highest specific cytotoxic T lymphocyte (CTL) induction rate at 4 weeks, using the ELISPOT test, cohorts were expanded to define the optimal dosing schedule for OTSGC-A24. RESULTS: In this study, 24 advanced gastric cancer patients with HLA-A*24:02 haplotype were enrolled and treated in 3 cohorts (3w cohort: 3; 2w cohort: 11 and 1w cohort: 10 patients). The most common adverse events were decreased appetite (29%), diarrhea (21%), myalgia (25%). The most common treatment-related adverse event was injection site erythema (25%). No dose-limiting toxicities were observed in any cohort and OTSGC-A24 was well tolerated. Positive CTL responses after vaccination were observed in 15 patients (75%) at 4 weeks: 3w cohort (33%), 2w cohort (88%), 1w cohort (78%). At 12 weeks, 18 patients had responded (90%); 3w cohort (100%), 2w cohort (100%), 1w cohort (78%). The best radiological was stable disease (40%). Median progression free survival was 1.7 months (95% CI: 1.4 to 3.5) and median overall survival was 5.7 months (95% CI 3.8 to 8.6). CONCLUSIONS: OTSGC-A24 combined peptide cancer vaccine was well tolerated. Significant responses in CTL were observed and the recommended phase 2 dose is 1 mg OTSGC-A24 sub-cutaneous, every 2 weeks. Although no radiological response was observed, a respectable overall survival was achieved, consistent with other immunotherapy agents being investigated in gastric cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01227772 , Date registered: 21 Oct 2010.
Assuntos
Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/terapia , Adulto , Idoso , Biomarcadores , Vacinas Anticâncer/efeitos adversos , Terapia Combinada , Citotoxicidade Imunológica , Feminino , Antígeno HLA-A24/genética , Antígeno HLA-A24/imunologia , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/uso terapêuticoRESUMO
BACKGROUND: Immunotherapy has become a promising treatment strategy for cancer. Immune checkpoint blockade with anti-CTLA4 mAb and anti-PD-1 mAb has demonstrated clear evidence of objective responses including improved overall survival and tumor shrinkage, driving renewed enthusiasm for cancer immunotherapy in multiple cancer types including esophageal squamous cell carcinoma (ESCC). There are several clinical trials using anti-PD1 mAb for ESCC in early phases and the results are currently promising. RESULTS AND CONCLUSIONS: In this review, recent advances in cancer immunotherapy for ESCC are discussed with particular focus on immune checkpoint inhibitors and cancer vaccine.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Imunoterapia/métodos , Anticorpos Monoclonais/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Carcinoma de Células Escamosas do Esôfago , Humanos , Terapia de Alvo Molecular/métodosRESUMO
Adoptive transfer of immune cells, such as T lymphocytes and NK cells, has potential to control cancer growth. However, this can be counteracted by immune escape mechanisms within the tumor microenvironment, including those mediated by reactive oxygen species (ROS). Here, we determined the levels of anti-oxidant molecules in NK cells and their capacity to overcome ROS-induced immune suppression. We investigated the effect of H2O2 on resting NK cells, IL-2-activated NK cells and NK cells expanded by coculture with the K562 leukemia cell line genetically modified to express membrane-bound IL-15 and 4-1BB ligand (K562-mb15-41BBL). Expression of anti-oxidant and anti-apoptotic genes was evaluated by expression array, and protein levels of anti-oxidant molecules by Western blot. Activated NK cells, IL-2-activated NK cells and NK cells expanded by K562-mb15-41BBL were significantly more resistant to H2O2-induced cell death than resting NK. Thioredoxin-1 (TXN1) and peroxiredoxin-1 (PRDX1) were also up-regulated in activated NK cells. Moreover, H2O2-induced cell death after IL-2 activation was significantly induced in the presence of an anti-TXN1-neutralising antibody. Collectively, these data document that activated NK cells can resist to H2O2-induced cell death by up-regulation of TXN1.
Assuntos
Células Matadoras Naturais/imunologia , Estresse Oxidativo/imunologia , Tiorredoxinas/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Humanos , Peróxido de Hidrogênio/farmacologia , Imunoterapia Adotiva , Interleucina-2/farmacologia , Células K562 , Células Matadoras Naturais/efeitos dos fármacos , Espécies Reativas de Oxigênio/imunologia , Regulação para CimaRESUMO
Therapeutic cancer vaccine enhances a specific immune response against tumor cells in vivo, resulting in exertion of antitumor effects. On the other hand, immune checkpoint inhibitors promote the induction of tumor-specific T cells and also enhance the cytotoxic abilityof these T cells in tumor microenvironment. There is a possibilitythat immune checkpoint inhibitors enhance tumor immune responses induced bytherapeutic cancer vaccine, and it is expected that additive or synergistic effects will be obtained bythe combination of them. Moreover, according to previous reports, we should use an immune checkpoint inhibitor to enhance the cytotoxic ability of tumor-specific T cells as the combination for therapeutic cancer vaccine. Furthermore, the combination of a specific antibodyagainst newlyidentified co-inhibitoryreceptors (Lag-3, Tim-3, TIGIT, etc)and a therapeutic cancer vaccine is also one of newlyexpected treatments in the future.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Imunoterapia , Neoplasias/terapia , Vacinas Anticâncer/imunologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologiaRESUMO
The response rate of anti-PD-1/anti-PD-L1antibody alone is about 20 to 30%and the development of biomarker for them is important to know their indication. Based on previous reports and our research results, we suggested that basic candidates of biomarker for anti-PD-1/anti-PD-L1antibody are the expression of PD-L1and HLA class I on cancer cells and the invasion of CD8 positive T cells in tumor microenvironment. Furthermore, in addition to these conditions, regulatory T cells and immune cells expressing PD-L1in tumor microenvironment, and microsatellite instability of cancer cells will be considered in the future.
Assuntos
Adaptação Biológica , Anticorpos/imunologia , Antígeno B7-H1/imunologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Microambiente TumoralRESUMO
Programmed cell death 1(PD-1)/PD-ligand 1(PD-L1)immune checkpoint blockade has emerged as a promising therapeutic strategy in various types of cancer. In a recent phase II clinical trial, treatment with the anti-PD-1 agent, pembrolizumab, resulted in considerable clinical benefit in patients with mismatch repair(MMR)-deficient colorectal cancer(CRC). Upregulation of PD-1on T-cells and PD-L1 on tumor cells induces inhibitory signals to suppress T-cell activation, leading to an immune-suppressive microenvironment particularly in MMR-deficient tumors. However, the regulation of PD-L1 expression on CRC cells is poorly understood. We hypothesized that certain microRNAs(miRNAs)are involved in the immunosuppressive microenvironment by directly targeting PD-L1. We identified candidate miRNAs by RNA-sequence analyses for mRNA and miRNA expression obtained from the TCGA colon adenocarcinoma database combined with miRNA target prediction programs. We found that forced miRNA expression could decrease PD-L1 expression on cancer cell lines. Our findings may facilitate an understanding of the role of miRNAs in PD-L1 regulation and also suggest potential miRNAs to serve as biomarkers and therapeutic targets for cancer immunotherapy.
Assuntos
Antígeno B7-H1/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , MicroRNAs/genética , Regulação Neoplásica da Expressão Gênica , HumanosRESUMO
HLA class I and PD-L1expressed on cancer cells play a pivotal role in the CTL recognition mechanism against cancer cells in the tumor microenvironment. It is well known that IFN-g upregulates PD-L1as well as HLA class I expression in cancer cells, and it is suggested that TILs, including CTL, produce IFN-g in the tumor microenvironment. Therefore, there is a possibility that IFN-g produced by activated TILs upregulate both HLA class I and PD-L1expression in cancer cells in the tumor microenvironment. We propose that the anti-tumor effect of CTL could be enhanced if the inhibition of CTL recognition mechanism against cancer cells via the PD-1/PD-L1pathway is canceled by anti-PD-1or anti-PD-L1antibody.
Assuntos
Antígeno B7-H1/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Neoplasias/imunologia , Microambiente Tumoral , Humanos , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Citotóxicos/imunologiaRESUMO
Downregulation of HLA class I expression may contribute to a poor prognosis in cancer patients. There is limited information about epigenetic and oncogenic regulation of HLA class I, and multiple mechanisms may be involved. In the current study, we examined the relationship between the HER2-signaling pathway (MAPK and PI3K-Akt) and the expression of HLA class I and Ag-processing machinery (APM) components. A panel of gastric and esophageal cancer cell lines was treated with wortmannin as an Akt-signal inhibitor; the MAPK signal inhibitor PD98059; lapatinib, which inhibits both the epidermal growth factor receptor and HER2 tyrosine kinase; or siRNA for MAPK. The levels of HER2-signaling molecules, APM components, and HLA class I were evaluated by Western blot, quantitative PCR, and flow cytometry. Resected gastric tumor tissues (n = 102) were analyzed for p-Erk and HLA class I expression by immunohistochemistry. As a result, inhibition of the MAPK pathway induced upregulation of HLA-A02 and HLA-A24 expression in parallel with an increase in APM components and enhanced target sensitivity to tumor Ag-specific CTL lysis. HLA-A expression was predominantly regulated by the MAPK pathway, but it was also influenced, in part, by the Akt pathway. There was a strong inverse correlation between p-Erk expression and HLA class I expression in clinical tumor samples. In conclusion, HLA-A expression is predominantly regulated by the MAPK pathway in gastric and esophageal cancer.
Assuntos
Antígenos de Neoplasias/biossíntese , Neoplasias Esofágicas/imunologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Antígenos HLA-A/biossíntese , Sistema de Sinalização das MAP Quinases/fisiologia , Neoplasias Gástricas/imunologia , Androstadienos/farmacologia , Apresentação de Antígeno/genética , Antígenos de Neoplasias/genética , Linhagem Celular Tumoral , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/antagonistas & inibidores , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Flavonoides/farmacologia , Genes MHC Classe I , Antígenos HLA-A/genética , Humanos , Lapatinib , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/fisiologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/fisiologia , Quinazolinas/farmacologia , RNA Interferente Pequeno/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , WortmaninaRESUMO
To develop more effective therapies for patients with advanced gastric cancer, we examined the potential of ex vivo expanded natural killer (NK) cells. We assessed the expression of ligands for NK Group 2 Member D (NKG2D, an important NK activation molecule) in primary tumors from 102 patients with gastric cancer by immunohistochemistry and determined their prognostic value. We then examined the in vitro and in vivo cytotoxicity of NK cells from healthy donors and patients with gastric cancer. The cytotoxicity of resting and of interleukin (IL)-2-activated NK cells was compared to that of NK cells expanded for 7 days by coculture with the K562-mb15-4.1BBL cell line. As a result, the expression of NKG2D ligands in primary tumors was correlated with favorable presenting features and outcomes, suggesting that gastric cancer may be sensitive to NK cell cytotoxicity. Although resting NK cells showed minimal cytotoxicity against gastric cancer cells, K562-mb15-4.1BBL-expanded NK cells were highly cytotoxic and significantly more powerful than IL-2-activated NK cells. Cytotoxicity was correlated with NKG2D ligand expression and could be modulated by mitogen-activated protein kinase and AKT-PI3 kinase inhibitors. The cytotoxicity of expanded NK cells against HER2-positive gastric cancer cells could be increased by Herceptin and further augmented by Lapatinib. Finally, expanded NK cells exhibited strong antitumor activity in immunodeficient mice engrafted with a gastric cancer cell line. In conclusion, gastric cancer tumors express NKG2D ligands and are highly susceptible to killing by NK cells stimulated by K562-mb15-4.1BBL. These results provide a strong rationale for clinical testing of these NK cells in patients and suggest their use to augment the effects of antibody therapy.
Assuntos
Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Neoplasias Gástricas/terapia , Animais , Citotoxicidade Celular Dependente de Anticorpos , Linhagem Celular Tumoral , Humanos , Interleucina-2/imunologia , Interleucina-2/farmacologia , Células K562 , Células Matadoras Naturais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Subfamília K de Receptores Semelhantes a Lectina de Células NK/biossíntese , Receptor ErbB-2/biossíntese , Neoplasias Gástricas/sangue , Neoplasias Gástricas/imunologiaRESUMO
Recently, we reported that human leukocyte antigen (HLA) class I expression is predominantly regulated by the mitogen-activated protein kinase (MAPK) pathway as one of the oncogenic regulations of HLA class I expression. In the present study, we examined mechanisms of how HLA class I and PD-L1 are regulated by MAPK inhibitors and interferon-γ (IFN-γ). Furthermore, we evaluated the expression of major signal transduction molecules by Western blot and anti-tumor CTL activity by a cytotoxic assay when HLA class I and PD-L1 were modulated by MAPK inhibitors and/or IFN-γ. As a result, we confirmed, as a more general phenomenon, that the inhibition of MAPK could upregulate HLA class I expression in a panel of human solid tumors (n = 26). Of note, we showed that MAPK inhibitors act on the upregulation of HLA class I expression through a different pathway from IFN-γ; there was an additive effect in the upregulation of HLA class I when treated with the combination of MAPK inhibitors and IFN-γ, and there was no overlapping activation of JAK2/STAT1 and Erk1/2 molecules when treated with either IFN-γ or MAPK inhibitors. Furthermore, we showed that IFN-γ-treatment impaired the tumor-specific CTL activity due to the upregulation of PD-L1 in spite of the upregulation of HLA class I, while MAPK inhibitors can augment the tumor-specific CTL activity due to the upregulated HLA class I without PD-L1 alterations. In conclusion, in addition to the original anti-proliferative activity, MAPK inhibitors may work toward the enhancement of T-cell-mediated anti-tumor immunity through the upregulation of HLA class I without the upregulation of PD-L1.
Assuntos
Antígeno B7-H1/fisiologia , Antígenos de Histocompatibilidade Classe I/fisiologia , Interferon gama/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Antígeno B7-H1/análise , Linhagem Celular Tumoral , Flavonoides/farmacologia , Humanos , Células Matadoras Naturais/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Regulação para CimaRESUMO
Overexpression of the receptor tyrosine kinases HER2 and HER3 is associated with a poor prognosis in several types of cancer. Presently, HER2- as well as HER3-targeted therapies are in clinical practice or evaluated within clinical trials, including treatment with mAbs mediating growth inhibition and/or activation of Ab-induced innate or adaptive cellular immunity. A better understanding of how HER2/HER3 signaling in tumors influences cellular immune mechanisms is therefore warranted. In this study, we demonstrate that HER2/HER3 signaling regulates the expression of MHC class I-related chain A and B (MICA and MICB) in breast cancer cell lines. The MICA and MICB (MICA/B) molecules act as key ligands for the activating receptor NK group 2, member D (NKG2D) and promote NK cell-mediated recognition and cytolysis. Genetic silencing of HER3 but not HER2 downregulated the expression of MICA/B, and HER3 overexpression significantly enhanced MICA expression. Among the major pathways activated by HER2/HER3 signaling, the PI3K/AKT pathway was shown to predominantly regulate MICA/B expression. Treatment with the HER3-specific ligand neuregulin 1ß promoted the expression in a process that was antagonized by pharmacological and genetic interference with HER3 but not by the ataxia-telangiectasia-mutated (ATM) and ATM and Rad3-related protein kinases inhibitor caffeine. These observations further emphasize that HER2/HER3 signaling directly, and not via genotoxic stress, regulates MICA/B expression. As anticipated, stimulating HER2/HER3 enhanced the NKG2D-MICA/B-dependent NK cell-mediated cytotoxicity. Taken together, we conclude that signaling via the HER2/HER3 pathway in breast carcinoma cell lines may lead to enhanced NKG2D-MICA/B recognition by NK cells and T cells.
Assuntos
Neoplasias da Mama/imunologia , Testes Imunológicos de Citotoxicidade , Antígenos de Histocompatibilidade Classe I/biossíntese , Células Matadoras Naturais/imunologia , Receptor ErbB-2/fisiologia , Receptor ErbB-3/fisiologia , Transdução de Sinais/imunologia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Testes Imunológicos de Citotoxicidade/métodos , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Sistema de Sinalização das MAP Quinases/imunologia , Receptor ErbB-2/biossíntese , Receptor ErbB-3/biossíntese , Transdução de Sinais/genética , Subpopulações de Linfócitos T/enzimologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Evasão Tumoral/genéticaRESUMO
The extracellular matrix protein biglycan (Bgn) is a leucine-rich proteoglycan that is involved in the matrix assembly, cellular migration and adhesion, cell growth, and apoptosis. Although a distinct expression of Bgn was found in a number of human tumors, the role of this protein in the initiation and/or maintenance of neoplastic transformation has not been studied in detail. Using an in vitro model of oncogenic transformation, a down-regulation of Bgn expression as well as an altered secretion of different Bgn isoforms was found both in murine and human HER-2/neu oncogene-transformed cells when compared with HER-2/neu(-) cells. This was associated with a reduced growth, wound closure, and migration capacity. Vice versa, silencing of Bgn in HER-2/neu(-) fibroblasts increased the growth rate and migration capacity of these cells. Bgn expression was neither modulated in HER-2/neu(+) cells by transforming growth factor-ß(1) nor by inhibition of the phosphoinositol 3-kinase and MAP kinase pathways. In contrast, inhibition of the protein kinase C (PKC) pathway led to the reconstitution of Bgn expression. In particular, the PKC target protein cAMP response element binding protein (CREB) is a major regulator of Bgn expression as the silencing of CREB by RNA interference was accompanied by â¼5000-fold increase in Bgn-mRNA expression in HER-2/neu(+) cells. Thus, Bgn inhibits the major properties of HER-2/neu-transformed cells, which is inversely modulated by the PKC signaling cascade.
Assuntos
Biglicano/metabolismo , Transformação Celular Neoplásica/metabolismo , Receptor ErbB-2/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/induzido quimicamente , Citometria de Fluxo , Humanos , Camundongos , Células NIH 3T3 , Receptor ErbB-2/genética , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
PURPOSE AND EXPERIMENTAL DESIGN: Although an increase in regulatory T cells (Tregs) is observed in tumor microenvironments, the underlying mechanism is not fully clarified. Since it was suggested that Tregs showed a lower sensitivity toward oxidative stress in comparison with conventional T cells, in the present study, we investigated the H(2)O(2) production and apoptosis of Tregs in gastric and esophageal cancer tissues, employing flow cytometric analysis using fresh samples (n = 93) and immunohistochemical analysis (n = 203). RESULTS: The increased tumor-infiltrating Tregs coexisted with elevated H(2)O(2) production according to disease progression. The grade of apoptosis in Tregs was less pronounced than that in conventional T cells, and there was a positive correlation between H(2)O(2) production and the grade of apoptosis in conventional T cells, while there was no correlation between H(2)O(2) production and the grade of apoptosis in Tregs. Moreover, Tregs were less sensitive to H(2)O(2)-induced apoptosis compared with conventional T cells in vitro. CONCLUSIONS: We have demonstrated that the increased prevalence of tumor-infiltrating Tregs closely related to their lower sensitivity to H(2)O(2)-induced apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Esofágicas/imunologia , Peróxido de Hidrogênio/farmacologia , Linfócitos do Interstício Tumoral/patologia , Neoplasias Gástricas/imunologia , Linfócitos T Reguladores/patologia , Idoso , Neoplasias Esofágicas/patologia , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Masculino , Oxidantes/farmacologia , Estresse Oxidativo/imunologia , Neoplasias Gástricas/patologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Trastuzumab has been recently approved for clinical use to treat HER2-expressing advanced gastric cancer, and anti-HER2-targeting therapy has become a promising option for gastric cancer. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and HER2. The aim of the present study was to explore the utility of lapatinib for gastric cancer, with a particular focus on trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC). METHODS: Nine gastric cancer cell lines were evaluated for the effects of lapatinib on the cell-surface accumulation of HER2 and analyzed for their additional effects on trastuzumab-mediated ADCC. Also, HER2 signaling with Western blot, proliferative function with the MTT assay, and apoptosis-inducing activity with 7ADD/Annexin-V were investigated when a panel of gastric cancer cell lines was treated with lapatinib. RESULTS: Lapatinib inhibited HER2 signaling and cell proliferation in the panel of gastric cancer cell lines. Lapatinib also induced the accumulation of HER2 on the cell surface, resulting in the enhancement of trastuzumab-mediated ADCC of gastric cancer. CONCLUSIONS: Lapatinib exhibits inhibitory activity in gastric cancer cells, and the combination of lapatinib with trastuzumab may be a promising treatment strategy for gastric cancer patients.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Quinazolinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Apoptose/efeitos dos fármacos , Western Blotting , Sinergismo Farmacológico , Citometria de Fluxo , Humanos , Lapatinib , Receptor ErbB-2/metabolismo , Trastuzumab , Células Tumorais CultivadasRESUMO
Although cancer immunotherapy using immune checkpoint inhibitors (ICIs) has been recognized as one of the major treatment modalities for malignant diseases, the clinical outcome is not uniform in all cancer patients. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells that possess various strong immunosuppressive activities involving multiple immunocompetent cells that are significantly accumulated in patients who did not respond well to cancer immunotherapies. We reviewed the perspective of MDSCs with emerging evidence in this review. Many studies on MDSCs were performed in malignant diseases. Substantial studies on the participation of MDSCs on non-malignant diseases such as chronic infection and autoimmune diseases, and physiological roles in obesity, aging, pregnancy and neonates have yet to be reported. With the growing understanding of the roles of MDSCs, variable therapeutic strategies and agents targeting MDSCs are being investigated, some of which have been used in clinical trials. More studies are required in order to develop more effective strategies against MDSCs.
Assuntos
Doenças Autoimunes , Células Supressoras Mieloides , Neoplasias , Gravidez , Feminino , Recém-Nascido , Humanos , Neoplasias/patologia , Imunoterapia , Células MieloidesRESUMO
Lapatinib is a dual tyrosine kinase inhibitor of the EGFR and HER2 tyrosine kinase domains. EGFR is expressed in 33.3% and HER2 in 30.3% of esophageal squamous cell carcinomas (ESCCs). To explore the potential utility of Lapatinib for therapy of ESCC patients, we evaluated the effect of Lapatinib on a panel of ESCC cell lines. EGFR and HER2 expression by the cell lines was established, and the effects of Lapatinib on inhibition of the phosphorylation of HER2, antiproliferative effect, apoptosis-inducing activity and accumulation of HER2 and EGFR on cell surface were evaluated. Additionally, the combined effect of Lapatinib together with Herceptin or Cetuximab on cell-mediated cytotoxicity was evaluated. Lapatinib inhibited HER2 phosphorylation in HER2-overexpressing, HER2 gene amplification positive ESCC cell line. Lapatinib also inhibited cell proliferation, induced apoptosis and caused the surface accumulation of HER2 and EGFR in ESCC cell lines. Addition of Lapatinib increased Herceptin-mediated antibody-dependent cell-mediated cytotoxicity by 15-25% with three ESCC target cell lines. Similarly, Cetuximab-mediated antibody-dependent cell-mediated cytotoxicity also increased by 15-30% in two ESCC cell lines on addition of Lapatinib. Cumulatively, the data indicate that Lapatinib has activity in EGFR- and/or HER2-expressing ESCC cells, and the combination therapy of Lapatinib and Cetuximab/Herceptin is a promising strategy in ESCC.
Assuntos
Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Neoplasias Esofágicas/genética , Genes erbB-2 , Neoplasias de Células Escamosas/genética , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Humanos , Lapatinib , Neoplasias de Células Escamosas/metabolismo , FosforilaçãoRESUMO
The HER2 oncogene is frequently over-expressed in human cancers and a promising target for immune therapy. Previous studies have shown that over-expression of mouse or rat HER2 leads to markedly reduced levels of major histocompatibility complex (MHC) class I and molecules of the antigen processing and presentation machinery (APM), thus resulting in a phenotype promoting tumor escape from the immune system. Our study focuses on analyzing the effect of HER2 on MHC class I antigen presentation and sensitivity to tumor-antigen specific cytotoxic T lymphocytes (CTLs) in HLA-A2.1(+) melanoma cell lines. We demonstrate significant inverse correlations both between the expression of HER2 and total MHC class I surface expression as well as between HER2 and HLA-A2. A significant reduction of HLA-A2 levels was found when melanoma and carcinoma cell lines were transfected with a human HER2 gene. A signaling-competent HER2 molecule was crucial for the observed HLA-A2 down-regulation, as transfectants expressing high levels of HER2 mutated in the tyrosine signaling domain did not show altered HLA-A2 expression. Importantly, the human melanoma cell line EST049 demonstrated reduced HER2 and melanoma antigen-specific recognition by CTLs upon HER2 transfection. In addition, high expression of HER2 prevented both IFN-γ mediated HLA-A2 up-regulation and improved recognition by HLA-A2-restricted CTLs in treated cells. Moreover, key APM molecules were down-regulated by HER2. These findings implicate that HER2 over-expressing tumors may be more prone to escape from HLA-A2 restricted CTLs suggesting that immunotherapy approaches inducing an integrated humoral, cellular and innate immune response would be most effective.
Assuntos
Antígenos de Neoplasias/imunologia , Genes erbB-2/fisiologia , Antígeno HLA-A2/imunologia , Melanoma/imunologia , Linfócitos T Citotóxicos/imunologia , Apresentação de Antígeno , Linhagem Celular Tumoral , Antígeno HLA-A2/análise , Humanos , Interferon gama/fisiologia , Melanoma/genética , Receptor ErbB-2/análise , Receptor ErbB-2/imunologia , Transdução de Sinais , Evasão TumoralRESUMO
Human NK cells can be divided into two subsets, CD56(dim)CD16(+)NK and CD56(bright)CD16(-)NK cells, based on their expression of CD56 and CD16. In the present study, we analyzed the relationship between CD56(dim)/CD56(bright) NK cells and H2O2 in tumor-infiltrating NK cells in patients with gastric (n = 50) and esophageal (n = 35) cancer. The ratio of CD56(dim) NK cells infiltrating tumors gradually decreased according to disease progression. H2O2 was abundantly produced within tumor microenvironments, and there was an inverse correlation between CD56(dim) NK cell infiltration and H2O2 production. CD56(dim) NK cells are more sensitive to apoptosis induced by physiological levels of H2O2 than CD56(bright) NK cells. Furthermore, the exposure of NK cells to H2O2 resulted in the impairment of ADCC activity. In conclusion, H2O2 produced within tumor microenvironments inversely correlated with the infiltration of CD56(dim) NK cells, possibly due to their preferentially induced cell death. These observations may explain one of the mechanisms behind NK cell dysfunction frequently observed in tumor microenvironments.