Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells

Manuel Colucci, Sara Zumerle, Silvia Bressan, Federico Gianfanti, Martina Troiani, Aurora Valdata, Mariantonietta D'Ambrosio, Emiliano Pasquini, Angelica Varesi, Francesca Cogo, Simone Mosole, Cristina Dongilli, Maria Andrea Desbats, Liliana Contu, Ajinkya Revankdar, Jingjing Chen, Madhuri Kalathur, Maria Luna Perciato, Rossella Basilotta, Laczko EndreStefan Schauer, Alaa Othman, Ilaria Guccini, Miriam Saponaro, Luisa Maraccani, Nicolò Bancaro, Ping Lai, Lei Liu, Nicolò Pernigoni, Federico Mele, Sara Merler, Lloyd C. Trotman, Greta Guarda, Bianca Calì, Monica Montopoli, Andrea Alimonti

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa). Reactivation of RARs triggers a robust senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of adapalene and docetaxel promotes a tumor-suppressive SASP that enhances natural killer (NK) cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of the allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in “immunologically cold” tumors.

Original languageEnglish
Pages (from-to)646-661.e9
JournalCancer Cell
Volume42
Issue number4
DOIs
StatePublished - 8 Apr 2024
Externally publishedYes

Keywords

  • AP-1
  • NK-Killing
  • RAR
  • SASP
  • adapalene
  • allogenic infusion
  • immunotherapy
  • metabolism
  • prostate cancer
  • senescence

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