Scientific publications

Modulation of tumor microenvironment by targeting histone acetylation in bladder cancer

Jan 4, 2024 | Magazine: Cell Death Discovery

Sandra P Nunes  1   2   3   4 , Lucia Morales  2   3   5 , Carolina Rubio  2   3   5 , Ester Munera-Maravilla  2   3   5 , Iris Lodewijk  2   3   5 , Cristian Suárez-Cabrera  2   3   5 , Victor G Martínez  2   3   5 , Mercedes Pérez-Escavy  2   3 , Miriam Pérez-Crespo  2   3   5 , Miguel Alonso Sánchez  2   3 , Esther Montesinos  2   3 , Edurne San José-Enériz  5   6 , Xabier Agirre  5   6 , Felipe Prósper  5   6   7 , Antonio Pineda-Lucena  8 , Rui Henrique  1   9   10 , Marta Dueñas  2   3   5 , Margareta P Correia  1   10 , Carmen Jerónimo  1   10 , Jesús M Paramio  11   12   13


Abstract

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.

CITATION  Cell Death Discov. 2024 Jan 4;10(1):1.  doi: 10.1038/s41420-023-01786-3