DataSheet_2_Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy.pdf

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.

免疫检查点治疗（Immune Checkpoint Therapy, ICT）已重塑了多种癌症的治疗格局，当前的前沿研究方向为发掘并开发新型联合疗法以提升治疗效果。此前，我们及其他研究团队已证实维A酸 (tretinoin) 对抗肿瘤免疫具有有益的调控作用。尽管已知维A酸可优先清除血液中的髓系来源抑制细胞，但目前对其在肿瘤微环境中的作用仍知之甚少，这阻碍了维A酸联合ICT的临床试验的合理设计。本研究旨在借助流式细胞术 (flow cytometry) 与RNA测序 (RNA-seq)，明确维A酸对小鼠肿瘤模型中肿瘤微环境的调控作用，并基于该结果确立维A酸联合多种ICT抗体在多种癌症模型中的最优给药剂量与给药方案。研究结果显示，维A酸可快速诱导以CD8+ T细胞浸润增多为特征的干扰素主导型炎性肿瘤微环境。该表型与ICT单独诱导的表型完全一致，且本研究证实联合使用维A酸可进一步放大该炎性微环境。维A酸的加入可显著提升抗CTLA-4/抗PD-L1联合疗法的治疗效果，且间隔给药方案的疗效优于同步给药方案，且该效果呈剂量依赖性。在多种癌症模型中，维A酸的积极作用同样适用于靶向OX40、GITR及CTLA-4的单药ICT抗体疗法。上述研究结果表明，维A酸可诱导出对ICT敏感的、干扰素驱动的CD8+ T细胞型肿瘤微环境。