Detalle Publicación

Modulation of tumor microenvironment by targeting histone acetylation in bladder cancer

Autores: Nunes, S. P.; Morales, L.; Rubio, C.; Munera-Maravilla, E.; Lodewijk, I.; Suárez-Cabrera, C.; Martínez, V. G.; Pérez-Escavy, M.; Pérez-Crespo, M.; Alonso-Sanchez, M.; Montesinos, E.; San José Enériz, Edurne; Agirre, X.; Prosper Cardoso, Felipe; Pineda Lucena, Antonio; Henrique, R.; Dueñas, M.; Correia, M. P.; Jerónimo, C.; Paramio, J. M. (Autor de correspondencia)
Título de la revista: CELL DEATH DISCOVERY
ISSN: 2058-7716
Volumen: 10
Número: 1
Páginas: 1
Fecha de publicación: 2024
Alterations in the epigenetic machinery in both tumor and immune cells contribute to bladder cancer (BC) development, constituting a promising target as an alternative therapeutic option. Here, we have explored the effects of a novel histone deacetylase (HDAC) inhibitor CM-1758, alone or in combination with immune checkpoint inhibitors (ICI) in BC. We determined the antitumor effects of CM-1758 in various BC cell lines together with the induction of broad transcriptional changes, with focus on the epigenetic regulation of PD-L1. Using an immunocompetent syngeneic mouse model of metastatic BC, we studied the effects of CM-1758 alone or in combination with anti-PD-L1 not only on tumor cells, but also in the tumor microenvironment. In vitro, we found that CM-1758 has cytotoxic and cytostatic effects either by inducing apoptosis or cell cycle arrest in BC cells at low micromolar levels. PD-L1 is epigenetically regulated by histone acetylation marks and is induced after treatment with CM-1758. We also observed that treatment with CM-1758 led to an important delay in tumor growth and a higher CD8 + T cell tumor infiltration. Moreover, anti-PD-L1 alone or in combination with CM-1758 reprogramed macrophage differentiation towards a M1-like polarization state and increased of pro-inflammatory cytokines systemically, yielding potential further antitumor effects. Our results suggest the possibility of combining HDAC inhibitors with immunotherapies for the management of advanced metastatic BC.