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Cancer Discov ; 14(7): 1252-1275, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38427556

RESUMO

Bone is the most common site of breast cancer metastasis. Bone metastasis is incurable and is associated with severe morbidity. Utilizing an immunocompetent mouse model of spontaneous breast cancer bone metastasis, we profiled the immune transcriptome of bone metastatic lesions and peripheral bone marrow at distinct metastatic stages, revealing dynamic changes during the metastatic process. We show that cross-talk between granulocytes and T cells is central to shaping an immunosuppressive microenvironment. Specifically, we identified the PD-1 and TIGIT signaling axes and the proinflammatory cytokine IL1ß as central players in the interactions between granulocytes and T cells. Targeting these pathways in vivo resulted in attenuated bone metastasis and improved survival, by reactivating antitumor immunity. Analysis of patient samples revealed that TIGIT and IL1ß are prominent in human bone metastasis. Our findings suggest that cotargeting immunosuppressive granulocytes and dysfunctional T cells may be a promising novel therapeutic strategy to inhibit bone metastasis. Significance: Temporal transcriptome profiling of the immune microenvironment in breast cancer bone metastasis revealed key communication pathways between dysfunctional T cells and myeloid derived suppressor cells. Cotargeting of TIGIT and IL1ß inhibited bone metastasis and improved survival. Validation in patient data implicated these targets as a novel promising approach to treat human bone metastasis.


Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Células Supressoras Mieloides , Receptores Imunológicos , Animais , Camundongos , Feminino , Neoplasias Ósseas/secundário , Neoplasias Ósseas/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/tratamento farmacológico , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Humanos , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Microambiente Tumoral/imunologia
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