RESUMO
(1) Background: The first line of treatment for recurrent/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has recently evolved with the approval of immunotherapies that target the anti-PD-1 immune checkpoint. However, only about 20% of the patients display a long-lasting objective tumor response. The modulation of cancer cell immunogenicity via a treatment-induced immunogenic cell death is proposed to potentially be able to improve the rate of patients who respond to immune checkpoint blocking immunotherapies. (2) Methods: Using human HNSCC cell line models and a mouse oral cancer syngeneic model, we have analyzed the ability of the EXTREME regimen (combination therapy using the anti-EGFR cetuximab antibody and platinum-based chemotherapy) to modify the immunogenicity of HNSCC cells. (3) Results: We showed that the combination of cetuximab and cisplatin reduces cell growth through both cell cycle inhibition and the induction of apoptotic cell death independently of p53. In addition, different components of the EXTREME regimen were found to induce, to a variable extent, and in a cell-dependent manner, the emission of mediators of immunogenic cell death, including calreticulin, HMGB1, and type I Interferon-responsive chemokines. Interestingly, cetuximab alone or combined with the IC50 dose of cisplatin can induce an antitumor immune response in vivo, but not when combined with a high dose of cisplatin. (4) Conclusions: Our observations suggest that the EXTREME protocol or cetuximab alone are capable, under conditions of moderate apoptosis induction, of eliciting the mobilization of the immune system and an anti-tumor immune response in HNSCC.
Assuntos
Cetuximab , Neoplasias de Cabeça e Pescoço , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose , Calreticulina , Cetuximab/uso terapêutico , Cisplatino/uso terapêutico , Proteína HMGB1 , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Imunidade , Interferon Tipo I , Camundongos , Recidiva Local de Neoplasia/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Proteína Supressora de Tumor p53RESUMO
The ventral hypothalamus acts to integrate visceral and systemic information to control energy balance. The basic helix-loop-helix transcription factor neurogenin-3 (Ngn3) is required for pancreatic ß-cell development and has been implicated in neuronal development in the hypothalamus. Here, we demonstrate that early embryonic hypothalamic inactivation of Ngn3 (also known as Neurog3) in mice results in rapid post-weaning obesity that is associated with hyperphagia and reduced energy expenditure. This obesity is caused by loss of expression of Pomc in Pomc- and Cart-expressing (Pomc/Cart) neurons in the arcuate nucleus, indicating an incomplete specification of anorexigenic first order neurons. Furthermore, following the onset of obesity, both the arcuate and ventromedial hypothalamic nuclei become insensitive to peripheral leptin treatment. This conditional mouse mutant therefore represents a novel model system for obesity that is associated with hyperphagia and underactivity, and sheds new light upon the roles of Ngn3 in the specification of hypothalamic neurons controlling energy balance.