RESUMO
BACKGROUND: Cancer cells subvert natural immunosuppression by upregulating the expression of checkpoint proteins and their ligands. For example, tumor cells expressing programmed death-ligand 1 (PD-L1) induce immune cell tolerance to cancers, thereby facilitating tumor progression. The recent clinical success of immunotherapy, particularly checkpoint blockade, represents a significant advance in cancer therapy. However, many cancers develop resistance to immunotherapies, and the underlying mechanisms and how these might be exploited to overcome resistance still need to be determined. METHODS: T cell dysfunction, in part caused by chronic T cell receptor stimulation, diminishes the capacity for durable responses to checkpoint blockade. Furthermore, T cell populations are phenotypically and functionally heterogeneous, resulting in varying responses to checkpoint blockade. Recent molecular studies of T cell heterogeneity have shown that checkpoint blockade on its own does not alter the epigenetic landscape of T cells, despite epigenetic changes governing T cell phenotype. CONCLUSION: Here we argue that epigenetic modifiers can be used to prime and sensitize T cells to immunotherapy. Administering epitherapy in conjunction with checkpoint blockade could decrease T cell exhaustion and immunotherapy resistance in many cancer types.
Assuntos
Epigênese Genética/imunologia , Inibidores de Checkpoint Imunológico/imunologia , Linfócitos T/imunologia , Animais , Antígeno B7-H1/imunologia , Humanos , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapiaRESUMO
DUSP6 is a dual-specificity phosphatase (DUSP) involved in breast cancer progression, recurrence, and metastasis. DUSP6 is predominantly cytoplasmic in HER2+ primary breast cancer cells, but the expression and subcellular localization of DUSPs, especially DUSP6, in HER2-positive circulating tumor cells (CTCs) is unknown. Here we used the DEPArray system to identify and isolate CTCs from metastatic triple negative breast cancer (TNBC) patients and performed single-cell NanoString analysis to quantify cancer pathway gene expression in HER2-positive and HER2-negative CTC populations. All TNBC patients contained HER2-positive CTCs. HER2-positive CTCs were associated with increased ERK1/ERK2 expression, which are direct DUSP6 targets. DUSP6 protein expression was predominantly nuclear in breast CTCs and the brain metastases but not pleura or lung metastases of TNBC patients. Therefore, nuclear DUSP6 may play a role in the association with cancer spreading in TNBC patients, including brain metastasis.
Assuntos
Biomarcadores Tumorais , Neoplasias Encefálicas/secundário , Fosfatase 6 de Especificidade Dupla/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Núcleo Celular/genética , Modelos Animais de Doenças , Fosfatase 6 de Especificidade Dupla/antagonistas & inibidores , Fosfatase 6 de Especificidade Dupla/metabolismo , Feminino , Imunofluorescência , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Invasividade Neoplásica , Estadiamento de Neoplasias , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Ligação Proteica , Transporte Proteico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Análise de Célula Única , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto , Fatores de Transcrição de p300-CBP/metabolismoRESUMO
The full epigenetic repertoire governing breast cancer metastasis is not completely understood. Here, we discuss the histone methyltransferase SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1) and its role in breast cancer metastasis. SETDB1 serves as an exemplar of the difficulties faced when developing therapies that not only specifically target cancer cells but also the more elusive and aggressive stem cells that contribute to metastasis via epithelial-to-mesenchymal transition and confer resistance to therapies.