一种新型的视黄酸受体-γ激动剂通过改变肺癌肿瘤免疫微环境来拮抗免疫检查点的耐药性。
A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment.
发表日期：2023 Sep 09
作者：
Cheng-Hsin Wei, Lu Huang, Blair Kreh, Xiuxia Liu, Liliya Tyutyunyk-Massey, Masanori Kawakami, Zibo Chen, Mi Shi, Serguei Kozlov, King C Chan, Thorkell Andresson, Mary Carrington, Vidyasagar Vuligonda, Martin E Sanders, Amir Horowitz, Patrick Hwu, Weiyi Peng, Ethan Dmitrovsky, Xi Liu
来源：
Cellular & Molecular Immunology
摘要：
维甲酸受体(RARs) 激动剂全反式维甲酸(ATRA)调控细胞生长、分化、免疫和存活。我们报告了ATRA治疗在同种免疫能力正常的小鼠中抑制了癌细胞的生长，但对免疫缺陷的小鼠没有此效果。肿瘤微环境被认为是一个因素：CD8+ T细胞耗竭对同种小鼠中ATRA的抗肿瘤效应产生了拮抗。同样，ATRA治疗与免疫检查点阻滞并没有合作抑制小鼠肺癌的生长。为增强ATRA的抗肿瘤效应而不促进其与肿瘤有关的潜力，我们使用了维甲酸受体γ(RARγ)激动剂(IRX4647)，因为它调控T细胞生物学。将IRX4647与免疫检查点(抗PD-L1)抑制剂联合治疗，在小鼠体内抑制了同种免疫能力正常344SQ肺癌，该模型对检查点具有抵抗力，其特点是基础T细胞和PD-L1表达较低。这种联合治疗明显增加了肿瘤微环境中CD4+ T细胞的存在，并增加了肿瘤中的IL-5和IL-13水平，同时降低了肿瘤基质中的CD38。在小鼠中，IL-5和/或IL-13的治疗增加了CD4+ T细胞而不是CD8+ T细胞。尽管RARγ表达在体外未明显影响肺癌生长情况，药代动力学分析发现IRX4647在小鼠中的半衰期为6小时。然而，RARα拮抗剂(IRX6696)-抗PD-L1联合治疗未能抑制同种小鼠肺癌的生长。综上所述，这些发现为临床试验提供了合理性，该试验旨在调查RARγ激动剂增强肿瘤对检查点阻断的响应。© 2023. Springer Nature Limited.
All-trans-retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment repressed cancer growth in syngeneic immunocompetent, but not immunodeficient mice. The tumor microenvironment was implicated: CD8+ T cell depletion antagonized ATRA's anti-tumorigenic effects in syngeneic mice. ATRA-treatment with checkpoint blockade did not cooperatively inhibit murine lung cancer growth. To augment ATRA's anti-tumorigenicity without promoting its pro-tumorigenic potential, an RARγ agonist (IRX4647) was used since it regulates T cell biology. Treating with IRX4647 in combination with an immune checkpoint (anti-PD-L1) inhibitor resulted in a statistically significant suppression of syngeneic 344SQ lung cancers in mice-a model known for its resistance to checkpoints and characterized by low basal T cell and PD-L1 expression. This combined treatment notably elevated CD4+ T-cell presence within the tumor microenvironment and increased IL-5 and IL-13 tumor levels, while simultaneously decreasing CD38 in the tumor stroma. IL-5 and/or IL-13 treatments increased CD4+ more than CD8+ T-cells in mice. IRX4647-treatment did not appreciably affect in vitro lung cancer growth, despite RARγ expression. Pharmacokinetic analysis found IRX4647 plasma half-life was 6 h in mice. Yet, RARα antagonist (IRX6696)-treatment with anti-PD-L1 did not repress syngeneic lung cancer growth. Together, these findings provide a rationale for a clinical trial investigating an RARγ agonist to augment check point blockade response in cancers.© 2023. Springer Nature Limited.