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1.
Proc Natl Acad Sci U S A ; 116(10): 4326-4335, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30770442

RESUMO

The combination of immune checkpoint blockade with chemotherapy is currently under investigation as a promising strategy for the treatment of triple negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) are the most prominent component of the breast cancer microenvironment because they influence tumor progression and the response to therapies. Here we show that macrophages acquire an immunosuppressive phenotype and increase the expression of programmed death ligand-1 (PD-L1) when treated with reactive oxygen species (ROS) inducers such as the glutathione synthesis inhibitor, buthionine sulphoximine (BSO), and paclitaxel. Mechanistically, these agents cause accumulation of ROS that in turn activate NF-κB signaling to promote PD-L1 transcription and the release of immunosuppressive chemokines. Systemic in vivo administration of paclitaxel promotes PD-L1 accumulation on the surface of TAMS in a mouse model of TNBC, consistent with in vitro results. Combinatorial treatment with paclitaxel and an anti-mouse PD-L1 blocking antibody significantly improved the therapeutic efficacy of paclitaxel by reducing tumor burden and increasing the number of tumor-associated cytotoxic T cells. Our results provide a strong rationale for the use of anti-PD-L1 blockade in the treatment of TNBC patients. Furthermore, interrogation of chemotherapy-induced PD-L1 expression in TAMs is warranted to define appropriate patient selection in the use of PD-L1 blockade.


Assuntos
Antígeno B7-H1/metabolismo , Imunossupressores/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Animais , Antígeno B7-H1/genética , Neoplasias da Mama/metabolismo , Butionina Sulfoximina/farmacologia , Linhagem Celular Tumoral , Quimiocinas , Tratamento Farmacológico , Feminino , Glutationa/metabolismo , Humanos , Camundongos , Paclitaxel/farmacologia , Fenótipo , RNA Mensageiro/metabolismo , Neoplasias de Mama Triplo Negativas , Microambiente Tumoral , Regulação para Cima
2.
Proc Natl Acad Sci U S A ; 116(9): 3604-3613, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30733286

RESUMO

Cancer cells have higher reactive oxygen species (ROS) than normal cells, due to genetic and metabolic alterations. An emerging scenario is that cancer cells increase ROS to activate protumorigenic signaling while activating antioxidant pathways to maintain redox homeostasis. Here we show that, in basal-like and BRCA1-related breast cancer (BC), ROS levels correlate with the expression and activity of the transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, ROS triggers AhR nuclear accumulation and activation to promote the transcription of both antioxidant enzymes and the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). In a mouse model of BRCA1-related BC, cancer-associated AhR and AREG control tumor growth and production of chemokines to attract monocytes and activate proangiogenic function of macrophages in the tumor microenvironment. Interestingly, the expression of these chemokines as well as infiltration of monocyte-lineage cells (monocyte and macrophages) positively correlated with ROS levels in basal-like BC. These data support the existence of a coordinated link between cancer-intrinsic ROS regulation and the features of tumor microenvironment. Therapeutically, chemical inhibition of AhR activity sensitizes human BC models to Erlotinib, a selective EGFR tyrosine kinase inhibitor, suggesting a promising combinatorial anticancer effect of AhR and EGFR pathway inhibition. Thus, AhR represents an attractive target to inhibit redox homeostasis and modulate the tumor promoting microenvironment of basal-like and BRCA1-associated BC.


Assuntos
Anfirregulina/genética , Proteína BRCA1/genética , Neoplasias da Mama/genética , Receptores de Hidrocarboneto Arílico/genética , Adulto , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Receptores ErbB/genética , Cloridrato de Erlotinib/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica , Homeostase/genética , Humanos , Camundongos , Pessoa de Meia-Idade , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/genética
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