RESUMEN
SIRT1 is a protein deacetylase with a broad range of biological functions, many of which are known to be important in carcinogenesis, however much of the literature regarding the role of SIRT1 in cancer remains conflicting. In this study we assessed the effect of SIRT1 on the initiation and progression of thymic T cell lymphomas. We employed mouse strains in which SIRT1 activity was absent or could be reversibly modulated in conjunction with thymic lymphoma induction using either the N-nitroso-N-methylurea (NMU) carcinogenesis or the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) transgene. Decreased SIRT1 activity reduced the development of thymic lymphomas in the NMU-treated mice but was permissive for the formation of lung adenomas. Conversely, in the NPM-ALK transgenic mice, decreased SIRT1 activity had a modest promoting effect in the development of thymic lymphomas. The results of the work presented here add to the growing body of evidence that sirt1 is neither an outright oncogene nor a tumor suppressor. These opposing results in two models of the same disease suggest that the influence of sirt1 on carcinogenesis may lie in a role in tumor surveillance.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Regulación Neoplásica de la Expresión Génica , Linfoma de Células T/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas/genética , Sirtuina 1/genética , Neoplasias del Timo/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/etiología , Adenocarcinoma del Pulmón/mortalidad , Administración Oral , Animales , Antineoplásicos Hormonales/farmacología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/etiología , Linfoma de Células T/mortalidad , Masculino , Metilnitrosourea/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Fusión Oncogénica/metabolismo , Especificidad de Órganos , Proteínas Tirosina Quinasas/metabolismo , Transducción de Señal , Sirtuina 1/metabolismo , Análisis de Supervivencia , Tamoxifeno/farmacología , Timo/efectos de los fármacos , Timo/metabolismo , Timo/patología , Neoplasias del Timo/tratamiento farmacológico , Neoplasias del Timo/etiología , Neoplasias del Timo/mortalidad , TransfecciónRESUMEN
Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.
Asunto(s)
Antígeno B7-H1/inmunología , Inmunoterapia , Células Asesinas Naturales/inmunología , Neoplasias Experimentales/terapia , Receptor de Muerte Celular Programada 1/inmunología , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Humanos , Células K562 , Células Asesinas Naturales/patología , Ratones , Ratones Noqueados , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genéticaRESUMEN
The protein deacetylase SIRT1 is involved in the regulation of a large number of cellular processes that are thought to be required for cancer initiation and progression. Both SIRT1 activity and tumorigenesis can be influenced by dietary fat and polyphenolics. We set out to determine whether dietary modulations of tumorigenesis are mediated by SIRT1 catalytic functions. We introduced a mammary gland tumor-inducing transgene, MMTV-PyMT, into stocks of mice bearing a H355Y point mutation in the Sirt1 gene that abolishes SIRT1 catalytic activity. Tumor latency was reduced in animals fed a high fat diet but this effect was not dependent on SIRT1 activity. Resveratrol had little effect on tumor formation except in animals heterozygous for the mutant Sirt1 gene. We conclude that the effects of these dietary interventions on tumorigenesis are not mediated by modulation of SIRT1 catalytic activity.
Asunto(s)
Transformación Celular Neoplásica/genética , Dieta Alta en Grasa , Mutación Puntual , Sirtuina 1/genética , Análisis de Varianza , Animales , Antígenos Transformadores de Poliomavirus/genética , Antineoplásicos Fitogénicos/farmacología , Biocatálisis , Transformación Celular Neoplásica/efectos de los fármacos , Heterocigoto , Masculino , Neoplasias Mamarias Experimentales/dietoterapia , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Virus del Tumor Mamario del Ratón/genética , Ratones Transgénicos , Resveratrol , Sirtuina 1/metabolismo , Estilbenos/farmacología , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genéticaRESUMEN
The protein deacetylase SIRT1 has been implicated in the regulation of a large number of cellular processes that are thought to be required for cancer initiation and progression. There are conflicting data that make it unclear whether Sirt1 functions as an oncogene or tumor suppressor. To assess the effect of SIRT1 on the emergence and progression of mammary tumors, we crossed mice that harbor a point mutation that abolishes SIRT1 catalytic activity with mice carrying the polyoma middle T transgene driven by the murine mammary tumor virus promoter (MMTV-PyMT). The absence of SIRT1 catalytic activity neither accelerated nor blocked the formation of tumors and metastases in this model. There was a lag in tumor latency that modestly extended survival in Sirt1 mutant mice that we attribute to a delay in mammary gland development and not to a direct effect of SIRT1 on carcinogenesis. These results are consistent with previous evidence suggesting that Sirt1 is not a tumor promoter or a tumor suppressor.