Novo protocolo de maturação de células dendríticas: linfócitos T e fatores de transcrição em metástases pulmonares de modelo experimental de carcinoma mamário

Abstract

Lung metastasis is a major contributor to mortality in breast cancer patients, accounting for more than 90% of disease-related deaths. Dendritic cells (DCs) play a central role in the activation of T lymphocytes against tumours, and their plasticity is modulated by stimuli received during maturation and by the tumour microenvironment. This makes DC-based immunotherapy a promising approach in the treatment of breast cancer and its complications, such as lung metastases. The aim of this study was to evaluate the effects of an alternative DC maturation protocol for immunotherapy using IL-12 and RANTES stimuli on tumour volume, reduction of lung metastases, lymphocyte infiltration and the prevalence of helper lymphocyte activation profiles. The biological effects of treatment with 4T1 in BALB/c mice with mammary carcinoma were demonstrated primarily by the reduction of lung metastases, quantified by the haematoxylin and eosin technique. Analysis of lung metastatic areas showed a significant reduction in the group treated with the alternative protocol (GP2) with an average of 1203.33 μm² compared to the tumour group (81052.5 μm²), with a p-value <0.0001 between the comparisons. Flow cytometric analysis of T lymphocyte infiltration in the tumour showed that the alternative protocol significantly increased the amount of helper lymphocytes, with a mean of 32.37 (MFI) compared to the GT (21.50) and GP1 (21.78) groups, with p-values <0.0001. Quantification of the transcription factors T-bet, GATA3, FOXP3 and RORγt in the tumour microenvironment showed that this protocol promotes a more profound modulation of the Th1 and Th17 pathways. Evaluation of cytotoxic and helper T lymphocytes in the lung showed that both treatments were effective in reducing inflammation-associated T cell infiltration. However, the animals treated with the alternative protocol showed a slight advantage in the reduction of transcription factors related to inflammation and immune regulation, such as T-bet, GATA3, FOXP3 and RORγt. Thus, the study highlights the importance of DCs in the induction of anti-tumour immune responses and suggests that the alternative protocol may be an effective strategy for modulating the immune response, thereby contributing to limiting the progression of lung metastases in breast cancer.