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1.
Nat Immunol ; 21(10): 1160-1171, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32747819

RESUMO

Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes increased the sensitivity of mouse mammary carcinoma cells to radiation therapy in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer.


Assuntos
Proteína 5 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/genética , Autofagia/genética , Neoplasias da Mama/radioterapia , DNA Mitocondrial/genética , Neoplasias Mamárias Animais/radioterapia , Mitocôndrias/metabolismo , Adulto , Idoso , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Feminino , Humanos , Interferon Tipo I/metabolismo , Neoplasias Mamárias Animais/genética , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Prognóstico , Tolerância a Radiação , Transdução de Sinais , Análise de Sobrevida
2.
Methods Enzymol ; 635: 111-125, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32122540

RESUMO

Focal radiation therapy has the potential to generate systemic tumor-targeting immune responses so potent as to eradicate anatomically distant, non-irradiated malignant lesions, a phenomenon commonly referred to as "the abscopal response." In cancer patients, bona fide abscopal responses are rare, although the recent introduction of immune checkpoint blockers into the clinical practice has significantly increased their incidence. In rodents, abscopal responses can be conveniently modeled by establishing two, slightly asynchronous and anatomically distant subcutaneous tumors in syngeneic immunocompetent hosts, provided that the therapeutic partners of radiation potentially included in the regimen of choice do not mediate systemic anticancer effects per se. Here, we describe such method to monitor abscopal responses based on mammary carcinoma TSA cells implanted in syngeneic immunocompetent BALB/c mice. With minor variations, the same technique can be conveniently applied to a variety of transplantable mouse tumors.


Assuntos
Camundongos Endogâmicos BALB C , Animais , Linhagem Celular Tumoral , Humanos , Camundongos
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