RESUMO
We have shown previously that phosphorylation of Mdm2 by ATM and c-Abl regulates Mdm2-p53 signaling and alters the effects of DNA damage in mice, including bone marrow failure and tumorigenesis induced by ionizing radiation. Here, we examine the physiological effects of Mdm2 phosphorylation by Akt, another DNA damage effector kinase. Surprisingly, Akt phosphorylation of Mdm2 does not alter the p53-mediated effects of ionizing radiation in cells or mice but regulates the p53 response to oxidative stress. Akt phosphorylation of Mdm2 serine residue 183 increases nuclear Mdm2 stability, decreases p53 levels, and prevents senescence in primary cells exposed to reactive oxidative species (ROS). Using multiple mouse models of ROS-induced cancer, we show that Mdm2 phosphorylation by Akt reduces senescence to promote KrasG12D-driven lung cancers and carcinogen-induced papilloma and hepatocellular carcinomas. Collectively, we document a unique physiologic role for Akt-Mdm2-p53 signaling in regulating cell growth and tumorigenesis in response to oxidative stress.
Assuntos
Neoplasias Induzidas por Radiação/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/efeitos da radiação , Carcinógenos/toxicidade , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Proliferação de Células/genética , Senescência Celular/efeitos dos fármacos , Senescência Celular/efeitos da radiação , Dano ao DNA/genética , Dano ao DNA/efeitos da radiação , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Neoplasias Induzidas por Radiação/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Papillomaviridae/patogenicidade , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismoRESUMO
Cancer therapies, including conventional chemotherapy, radiation, and molecularly targeted agents, can lead to tumor eradication through a variety of mechanisms. In addition to their effects on tumor cell growth and survival, these regimens can also influence the surrounding tumor-immune microenvironment in ways that ultimately impact therapy responses. A unique biological outcome of cancer therapy is induction of cellular senescence. Senescence is a damage-induced stress program that leads to both the durable arrest of tumor cells and remodeling the tumor-immune microenvironment through activation of a collection pleiotropic cytokines, chemokines, growth factors, and proteinases known as the senescence-associated secretory phenotype (SASP). Depending on the cancer context and the mechanism of action of the therapy, the SASP produced following therapy-induced senescence (TIS) can promote anti-tumor immunity that enhances therapeutic efficacy, or alternatively chronic inflammation that leads to therapy failure and tumor relapse. Thus, a deeper understanding of the mechanisms regulating the SASP and components necessary for robust anti-tumor immune surveillance in different cancer and therapy contexts are key to harnessing senescence for tumor control. Here we draw a roadmap to modulate TIS and its immune-stimulating features for cancer immunotherapy.
Assuntos
Senescência Celular , Neoplasias , Humanos , Fenótipo , Senescência Celular/genética , Neoplasias/patologia , Imunoterapia , Microambiente TumoralRESUMO
Pancreatic ductal adenocarcinoma has quickly risen to become the 3rd leading cause of cancer-related death. This is in part due to its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here we investigated an innovative immunotherapy approach combining local delivery of STING and TLR4 innate immune agonists via lipid-based nanoparticles (NPs) co-encapsulation with senescence-inducing RAS-targeted therapies that can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other pro-inflammatory signaling, increased antigen presentation by tumor cells and antigen presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and Type I interferon-dependent tumor regressions and long-term survival in preclinical PDAC models. STING and TLR4-mediated Type I interferon signaling were also associated with enhanced NK and CD8+ T cell immunity in human PDAC. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can synergize to orchestrate a coordinated innate and adaptive immune assault to overcome immune suppression and activate durable anti-tumor T cell responses against PDAC.
RESUMO
Immunotherapies that produce durable responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of the senescence-associated secretory phenotype (SASP) can be an effective approach to activate anti-tumor natural killer (NK) cell and T cell immunity. In the present study, we found that the pancreas tumor microenvironment suppresses NK cell and T cell surveillance after therapy-induced senescence through enhancer of zeste homolog 2 (EZH2)-mediated epigenetic repression of proinflammatory SASP genes. EZH2 blockade stimulated production of SASP chemokines CCL2 and CXCL9/10, leading to enhanced NK cell and T cell infiltration and PDAC eradication in mouse models. EZH2 activity was also associated with suppression of chemokine signaling and cytotoxic lymphocytes and reduced survival in patients with PDAC. These results demonstrate that EZH2 represses the proinflammatory SASP and that EZH2 inhibition combined with senescence-inducing therapy could be a powerful means to achieve immune-mediated tumor control in PDAC.