RESUMO
Inflammation affects tumor immune surveillance and resistance to therapy. Here, we show that production of IL1ß in primary breast cancer tumors is linked with advanced disease and originates from tumor-infiltrating CD11c+ myeloid cells. IL1ß production is triggered by cancer cell membrane-derived TGFß. Neutralizing TGFß or IL1 receptor prevents breast cancer progression in humanized mouse model. Patients with metastatic HER2- breast cancer display a transcriptional signature of inflammation in the blood leukocytes, which is attenuated after IL1 blockade. When present in primary breast cancer tumors, this signature discriminates patients with poor clinical outcomes in two independent public datasets (TCGA and METABRIC).Significance: IL1ß orchestrates tumor-promoting inflammation in breast cancer and can be targeted in patients using an IL1 receptor antagonist. Cancer Res; 78(18); 5243-58. ©2018 AACRSee related commentary by Dinarello, p. 5200.
Assuntos
Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/metabolismo , Transcrição Gênica , Animais , Neoplasias da Mama/tratamento farmacológico , Antígeno CD11c/metabolismo , Capecitabina/administração & dosagem , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Feminino , Furanos/administração & dosagem , Humanos , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Cetonas/administração & dosagem , Leucócitos Mononucleares/citologia , Macrófagos/metabolismo , Camundongos , Camundongos SCID , Células Mieloides/metabolismo , Metástase Neoplásica , Transplante de Neoplasias , Paclitaxel/administração & dosagem , Projetos Piloto , Fator de Crescimento Transformador beta/metabolismoRESUMO
Although a fraction of human blood memory CD4(+) T cells expresses chemokine (C-X-C motif) receptor 5 (CXCR5), their relationship to T follicular helper (Tfh) cells is not well established. Here we show that human blood CXCR5(+)CD4(+) T cells share functional properties with Tfh cells and appear to represent their circulating memory compartment. Blood CXCR5(+)CD4(+) T cells comprised three subsets: T helper 1 (Th1), Th2, and Th17 cells. Th2 and Th17 cells within CXCR5(+), but not within CXCR5(-), compartment efficiently induced naive B cells to produce immunoglobulins via interleukin-21 (IL-21). In contrast, Th1 cells from both CXCR5(+) and CXCR5(-) compartments lacked the capacity to help B cells. Patients with juvenile dermatomyositis, a systemic autoimmune disease, displayed a profound skewing of blood CXCR5(+) Th cell subsets toward Th2 and Th17 cells. Importantly, the skewing of subsets correlated with disease activity and frequency of blood plasmablasts. Collectively, our study suggests that an altered balance of Tfh cell subsets contributes to human autoimmunity.