RESUMO
Brain metastases, including prevalent breast-to-brain metastasis (B2BM), represent an urgent unmet medical need in the care of cancer due to a lack of effective therapies. Immune evasion is essential for cancer cells to metastasize to the brain tissue for brain metastasis. However, the intrinsic genetic circuits that enable cancer cells to avoid immune-mediated killing in the brain microenvironment remain poorly understood. Here, we report that a brain-enriched long noncoding RNA (BMOR) expressed in B2BM cells is required for brain metastasis development and is both necessary and sufficient to drive cancer cells to colonize the brain tissue. Mechanistically, BMOR enables cancer cells to evade immune-mediated killing in the brain microenvironment for the development of brain metastasis by binding and inactivating IRF3. In preclinical brain metastasis murine models, locked nucleic acid-BMOR, a designed silencer targeting BMOR, is effective in suppressing the metastatic colonization of cancer cells in the brain for brain metastasis. Taken together, our study reveals a mechanism underlying B2BM immune evasion during cancer cell metastatic colonization of brain tissue for brain metastasis, where B2BM cells evade immune-mediated killing in the brain microenvironment by acquiring a brain-enriched long noncoding RNA genetic feature.
Assuntos
Neoplasias Encefálicas , Encéfalo , Neoplasias da Mama , Evasão da Resposta Imune , RNA Longo não Codificante , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/secundário , Mama/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Evasão da Resposta Imune/genética , Camundongos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Microambiente TumoralRESUMO
Breast cancer is the most common cancer, with the highest mortality rate and the most diagnosed cancer type in women worldwide. To identify the effect innate immune checkpoint for breast cancer immunotherapy, the innate immune prognostic biomarkers were selected through the ICI score model and the risk model in breast cancer patients. Moreover, the reliability and accuracy of the ICI score model and the risk model were further examined through the analysis of breast cancer prognosis and immune cell infiltration. The pan cancer analysis further confirmed and selected CXCL9 as the key innate immune checkpoint for breast cancer immunotherapy and identified three small molecular drugs for target CXCL9 through molecular docking analysis. In summary, CXCL9 significantly correlated with the prognostic of breast cancer and immune cell infiltration and could be innate immune checkpoint for breast cancer immunotherapy.
