Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer
Manuel Colucci1, Sara Zumerle2, Silvia Bressan3
1Institute of Oncology Research (IOR), CH6500 Bellinzona, Switzerland; Università della Svizzera Italiana, CH6900 Lugano, Switzerland; Faculty of Biology and Medicine, University of Lausanne UNIL, CH1011 Lausanne, Switzerland.
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.
Insights
Adapalene, a retinoic acid receptor agonist, induces tumor-suppressive senescence in prostate cancer. Combining it with docetaxel enhances natural killer cell anti-tumor activity, offering a novel immunotherapy strategy.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Cellular senescence has dual roles in tumors, influenced by the senescence-associated secretory phenotype (SASP).
- Therapeutic strategies aim to harness tumor-suppressive SASP factors while mitigating tumor-promoting ones.
- Prostate cancer (PCa) presents a clinical challenge in modulating senescence for therapeutic benefit.
Purpose of the Study:
- To identify compounds that induce a tumor-suppressive SASP in prostate cancer.
- To evaluate the efficacy of adapalene, a retinoic acid receptor (RAR) agonist, in promoting cancer cell senescence.
- To assess the combination therapy of adapalene and docetaxel in enhancing anti-tumor immunity.
Main Methods:
- Utilized adapalene to target RARs and induce senescence in prostate cancer cells.
- Investigated the SASP profile induced by adapalene, focusing on tumor-suppressive factors.
- Tested the combination of adapalene and docetaxel in preclinical mouse models of PCa.
- Assessed the impact of the combination therapy on natural killer (NK) cell-mediated tumor clearance and allogenic NK cell infusion efficacy.
Main Results:
- Adapalene effectively induced cellular senescence and a tumor-suppressive SASP in PCa.
- The combination of adapalene and docetaxel synergistically promoted a tumor-suppressive SASP.
- This combination therapy significantly enhanced NK cell-mediated tumor clearance in preclinical models.
- The approach improved the efficacy of allogenic human NK cell infusion in mice with human PCa xenografts.
Conclusions:
- Adapalene is a potent pro-senescence agent for prostate cancer, inducing a beneficial SASP.
- Combination therapy with adapalene and docetaxel enhances NK cell anti-tumor immunity.
- This strategy offers a promising approach to stimulate anti-tumor immune responses in "immunologically cold" tumors.
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