RESUMO
New strategies for cancer immunotherapy are needed since most solid tumors do not respond to current approaches. Here we used epithelial cell adhesion molecule EpCAM (a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells) aptamer-linked small-interfering RNA chimeras (AsiCs) to knock down genes selectively in EpCAM+ tumors with the goal of making cancers more visible to the immune system. Knockdown of genes that function in multiple steps of cancer immunity was evaluated in aggressive triple-negative and HER2+ orthotopic, metastatic, and genetically engineered mouse breast cancer models. Gene targets were chosen whose knockdown was predicted to promote tumor neoantigen expression (Upf2, Parp1, Apex1), phagocytosis, and antigen presentation (Cd47), reduce checkpoint inhibition (Cd274), or cause tumor cell death (Mcl1). Four of the six AsiC (Upf2, Parp1, Cd47, and Mcl1) potently inhibited tumor growth and boosted tumor-infiltrating immune cell functions. AsiC mixtures were more effective than individual AsiC and could synergize with anti-PD-1 checkpoint inhibition.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno CD47/genética , Molécula de Adesão da Célula Epitelial/genética , Neoplasias Mamárias Experimentais/terapia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Poli(ADP-Ribose) Polimerase-1/genética , Proteínas de Ligação a RNA/genética , Animais , Apresentação de Antígeno/efeitos dos fármacos , Antineoplásicos Imunológicos/química , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/imunologia , Aptâmeros de Nucleotídeos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CD47/antagonistas & inibidores , Antígeno CD47/imunologia , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/antagonistas & inibidores , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/imunologia , Molécula de Adesão da Célula Epitelial/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoconjugados/química , Imunoconjugados/imunologia , Imunoconjugados/farmacologia , Imunoterapia/métodos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Terapia de Alvo Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/imunologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Fagocitose/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/imunologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/imunologia , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia , Carga Tumoral/efeitos dos fármacosRESUMO
Screening methods of High-Grade Serous Ovarian Cancer (HGSOC) lack specificity and sensitivity, partly due to benign tumors producing false-positive findings. We utilized a differential expression analysis pipeline on malignant tumor (MT) and normal epithelial (NE) samples, and also filtered the results to discriminate between MT and benign tumor (BT). We report that a panel of 26 dysregulated genes stratifies MT from both BT and NE. We further validated our findings by utilizing unsupervised clustering methods on two independent datasets. We show that the 26-genes panel completely distinguishes HGSOC from NE, and produces a more accurate classification between HGSOC and BT. Pathway analysis reveals that AKT3 is of particular significance, because of its high fold change and appearance in the majority of the dysregulated pathways. mRNA patterns of AKT3 suggest essential connections with tumor growth and metastasis, as well as a strong biomarker potential when used with 3 other genes (PTTG1, MND1, CENPF). Our results show that dysregulation of the 26-mRNA signature panel provides an evidence of malignancy and contribute to the design of a high specificity biomarker panel for detection of HGSOC, potentially in an early more curable stage.