RESUMO
Although immune-based therapies have revolutionized the management of cancer, novel approaches are urgently needed to improve their outcome. We investigated the role of endogenous steroids in the resistance to cancer immunotherapy, as these have strong immunomodulatory functions. Using a publicly available database, we found that the intratumoral expression of 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1), which regenerates inactive glucocorticoids into active glucocorticoids, was associated with poor clinical outcome and correlated with immunosuppressive gene signatures in patients with renal cell carcinoma (RCC). HSD11B1 was mainly expressed in tumor-infiltrating immune myeloid cells as seen by immunohistochemistry in RCC patient samples. Using peripheral blood mononuclear cells from healthy donors or immune cells isolated from the tumor of RCC patients, we showed that the pharmacological inhibition of HSD11B1 improved the response to the immune checkpoint inhibitor anti-PD-1. In a subcutaneous mouse model of renal cancer, the combination of an HSD11B1 inhibitor with anti-PD-1 treatment increased the proportion of tumor-infiltrating dendritic cells. In an intrarenal mouse tumor model, HSD11B1 inhibition increased the survival of mice treated with anti-PD-1. In addition, inhibition of HSD11B1 sensitized renal tumors in mice to immunotherapy with resiquimod, a Toll-like receptor 7 agonist. Mechanistically, we demonstrated that HSD11B1 inhibition combined with resiquimod increased T cell-mediated cytotoxicity to tumor cells by stimulating the antigen-presenting capacity of dendritic cells. In conclusion, these results support the use of HSD11B1 inhibitors to improve the outcome of immunotherapy in renal cancer and highlight the role of the endogenous glucocorticoid metabolism in the efficacy of immunotherapy.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Animais , Camundongos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Glucocorticoides/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Leucócitos Mononucleares/metabolismo , Neoplasias Renais/tratamento farmacológico , Imunidade , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismoRESUMO
BACKGROUND & AIMS: Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in specific cancers. Herein, we investigated how TTP contributes to the development of liver inflammation and fibrosis, which are key drivers of hepatocarcinogenesis, as well as to the onset and progression of hepatocellular carcinoma (HCC). METHODS: TTP expression was investigated in mouse/human models of hepatic metabolic diseases and cancer. The role of TTP in nonalcoholic steatohepatitis and HCC development was further examined through in vivo/vitro approaches using liver-specific TTP knockout mice and a panel of hepatic cancer cells. RESULTS: Our data demonstrate that TTP loss in vivo strongly restrains development of hepatic steatosis and inflammation/fibrosis in mice fed a methionine/choline-deficient diet, as well as HCC development induced by the carcinogen diethylnitrosamine. In contrast, low TTP expression fostered migration and invasion capacities of in vitro transformed hepatic cancer cells likely by unleashing expression of key oncogenes previously associated with these cancerous features. Consistent with these data, TTP was significantly down-regulated in high-grade human HCC, a feature further correlating with poor clinical prognosis. Finally, we uncover hepatocyte nuclear factor 4 alpha and early growth response 1, two key transcription factors lost with hepatocyte dedifferentiation, as key regulators of TTP expression. CONCLUSIONS: Although TTP importantly contributes to hepatic inflammation and cancer initiation, its loss with hepatocyte dedifferentiation fosters cancer cells migration and invasion. Loss of TTP may represent a clinically relevant biomarker of high-grade HCC associated with poor prognosis.
Assuntos
Carcinoma Hepatocelular/genética , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Tristetraprolina/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Dietilnitrosamina/administração & dosagem , Dietilnitrosamina/toxicidade , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Hepatócitos , Humanos , Fígado/imunologia , Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/química , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica , Cultura Primária de Células , Prognóstico , RNA-Seq , Análise de Sobrevida , Tristetraprolina/genéticaRESUMO
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor arising in the mesothelium that covers the lungs, the heart, and the thoracic cavity. MPM development is mainly associated with asbestos. Treatments provide only modest survival since the median survival average is 9-18 months from the time of diagnosis. Therefore, more effective treatments must be identified. Most data describing new therapeutic targets were obtained from in vitro experiments and need to be validated in reliable in vivo preclinical models. This article describes one such reliable MPM orthotopic model obtained after injection of a human MPM cell line H2052/484 into the pleural cavity of immunodeficient athymic mice. Transplantation in the orthotopic site allows studying the progression of tumor in the natural in vivo environment. Positron emission tomography/computed tomography (PET/CT) molecular imaging using the clinical [18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG) radiotracer is the diagnosis method of choice for examining patients with MPM. Accordingly, [18F]FDG-PET/CT was used to longitudinally monitor the disease progression of the H2052/484 orthotopic model. This technique has a high 3R potential (Reduce the number of animals, Refine to lessen pain and discomfort, and Replace animal experimentation with alternatives) since the tumor development can be monitored non-invasively and the number of animals required could be significantly reduced. This model displays a high development rate, a rapid tumor growth, is cost-efficient and allows for rapid clinical translation. By using this orthotopic xenograft MPM model, researchers can assess biological responses of a reliable MPM model following therapeutic interventions.