瑞士肿瘤研究所(IOR)Andrea Alimonti团队近期取得重要工作进展，他们研究提出，视黄酸受体激活可重编程衰老反应并增强自然杀伤细胞的抗肿瘤活性。相关研究成果2024年2月29日在线发表于《癌细胞》杂志上。

据介绍，细胞衰老可以在肿瘤中发挥双重作用，抑制或促进肿瘤进展。衰老细胞释放的衰老相关分泌表型（SASP）在这种分化中起着至关重要的作用。因此，临床挑战在于开发安全增强癌症衰老的疗法，支持肿瘤抑制性SASP因子而非肿瘤促进因子。

研究人员确定了视黄酸受体（RAR）激动剂阿达帕林是一种在前列腺癌症（PCa）中有效的促衰老化合物。RAR的再激活会触发强大的衰老反应和肿瘤抑制性SASP。在PCa的临床前小鼠模型中，阿达帕林和多西他赛的组合促进了肿瘤抑制性SASP，该SASP比单独使用任何一种药物都更有效地增强了自然杀伤（NK）细胞介导的肿瘤清除率。

总之，这种方法提高了同种异体输注人NK细胞对注射了人PCa细胞小鼠的疗效，提示了在“免疫冷”肿瘤中刺激抗肿瘤免疫反应的替代治疗策略。

附：英文原文

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

Author: 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 Endre, Stefan 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

Issue&Volume: 2024-02-29

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.

DOI: 10.1016/j.ccell.2024.02.004

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00048-5