Tilsed Caitlin M, Casey Thomas H, de Jong Emma, Bosco Anthony, Zemek Rachael M, Salmons Joanne, Wan Graeme, Millward Michael J, Nowak Anna K, Lake Richard A, Lesterhuis Willem Joost
School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia.
National Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, Australia.
Front Oncol. 2022 Mar 24;12:849793. doi: 10.3389/fonc.2022.849793. eCollection 2022.
With immune checkpoint therapy (ICT) having reshaped the treatment of many cancers, the next frontier is to identify and develop novel combination therapies to improve efficacy. Previously, we and others identified beneficial immunological effects of the vitamin A derivative tretinoin on anti-tumour immunity. Although it is known that tretinoin preferentially depletes myeloid derived suppressor cells in blood, little is known about the effects of tretinoin on the tumour microenvironment, hampering the rational design of clinical trials using tretinoin in combination with ICT. Here, we aimed to identify how tretinoin changed the tumour microenvironment in mouse tumour models, using flow cytometry and RNAseq, and we sought to use that information to establish optimal dosing and scheduling of tretinoin in combination with several ICT antibodies in multiple cancer models. We found that tretinoin rapidly induced an interferon dominated inflammatory tumour microenvironment, characterised by increased CD8+ T cell infiltration. This phenotype completely overlapped with the phenotype that was induced by ICT itself, and we confirmed that the combination further amplified this inflammatory milieu. The addition of tretinoin significantly improved the efficacy of anti-CTLA4/anti-PD-L1 combination therapy, and staggered scheduling was more efficacious than concomitant scheduling, in a dose-dependent manner. The positive effects of tretinoin could be extended to ICT antibodies targeting OX40, GITR and CTLA4 monotherapy in multiple cancer models. These data show that tretinoin induces an interferon driven, CD8+ T cell tumour microenvironment that is responsive to ICT.
随着免疫检查点疗法（ICT）重塑了多种癌症的治疗方式，下一个前沿领域是识别和开发新型联合疗法以提高疗效。此前，我们和其他人发现维生素A衍生物维甲酸对抗肿瘤免疫具有有益的免疫效应。尽管已知维甲酸优先消耗血液中的髓源性抑制细胞，但关于维甲酸对肿瘤微环境的影响知之甚少，这阻碍了使用维甲酸与ICT联合进行临床试验的合理设计。在此，我们旨在通过流式细胞术和RNA测序确定维甲酸如何在小鼠肿瘤模型中改变肿瘤微环境，并试图利用这些信息在多种癌症模型中确定维甲酸与几种ICT抗体联合使用时的最佳给药剂量和给药方案。我们发现维甲酸迅速诱导了以干扰素为主导的炎性肿瘤微环境，其特征是CD8 + T细胞浸润增加。这种表型与ICT本身诱导的表型完全重叠，并且我们证实联合使用进一步放大了这种炎性环境。在剂量依赖性方面，添加维甲酸显著提高了抗CTLA4 /抗PD-L1联合疗法的疗效，并且交错给药方案比同时给药方案更有效。维甲酸的积极作用可以扩展到针对多种癌症模型中OX40、GITR和CTLA4单药治疗的ICT抗体。这些数据表明，维甲酸诱导了对ICT有反应的、由干扰素驱动的、CD8 + T细胞肿瘤微环境。
