Yamada-Hara Miki, Amaya Lauren, Wang Zhihe, Byun Ji Won, Takahashi Naoki, Sharma Sunandini, Chang Han, Tanaka Arisachi, Zeng Liping, Malakoutikhah Zahra, Ganguly Sneha, Vu Minh-Chau, Levin Matt, Schwartz David, Heath Jack, Herdman Scott, Corr Maripat, Raz Eyal, Bertin Samuel
University of California, San Diego, La Jolla, CA, United States.
Cell IDx (United States), San Diego, CA, United States.
Cancer Immunol Res. 2025 Jun 18. doi: 10.1158/2326-6066.CIR-24-1128.
The retinoic acid receptor-related orphan receptor C (RORC) gene encodes two isoforms, RORγ and RORγt, which function as transcription factors in different cell types. RORγt is expressed in specific immune cells involved in inflammatory responses, while RORγ is found in parenchymal cells, where it participates in metabolism and circadian rhythm regulation. Although the roles of RORγt in CD4+ T-helper 17 (Th17) lymphocytes and RORγ in certain cancer cell types are increasingly recognized, their relative contributions to lung cancer (LC) development remain unclear. In this study, we investigated the roles of RORC, RORγ, and RORγt in LC using mouse models and human data from The Cancer Genome Atlas (TCGA). We evaluated the effects of Rorc gene deletion and RORγ/γt pharmacological inhibition in cancer and immune cells in vitro and in vivo. Pharmacological blockade of RORγ/γt with digoxin significantly reduced LC development in two mouse models: a KrasG12D-driven genetic model and a urethane-induced chemical model. Mechanistically, this effect was mediated by inhibition of RORγt in specific immune cells, such as type 3 innate lymphoid cells (ILC3s) and Th17 cells, rather than by inhibiting RORγ in tumor cells. This reduced the production of pro-inflammatory cytokines, including interleukin-17A (IL-17A), IL-17F, and IL-22, and decreased tumor cell proliferation. Additionally, TCGA analysis revealed that elevated RORC expression is associated with an altered tumor microenvironment (TME) and poorer prognosis in patients with lung adenocarcinoma (LUAD). These findings highlight the therapeutic potential of targeting RORγt to reduce pro-tumor inflammation and propose a strategy for LC treatment.
维甲酸受体相关孤儿受体C（RORC）基因编码两种亚型，即RORγ和RORγt，它们在不同细胞类型中作为转录因子发挥作用。RORγt在参与炎症反应的特定免疫细胞中表达，而RORγ则存在于实质细胞中，参与代谢和昼夜节律调节。尽管RORγt在CD4 +辅助性T细胞17（Th17）淋巴细胞中的作用以及RORγ在某些癌细胞类型中的作用越来越受到认可，但其对肺癌（LC）发展的相对贡献仍不清楚。在本研究中，我们使用小鼠模型和来自癌症基因组图谱（TCGA）的人类数据，研究了RORC、RORγ和RORγt在LC中的作用。我们评估了Rorc基因缺失和RORγ/γt药理抑制在体外和体内对癌细胞和免疫细胞的影响。用地高辛对RORγ/γt进行药理阻断，在两种小鼠模型中显著降低了LC的发展：一种是KrasG12D驱动的遗传模型，另一种是尿烷诱导的化学模型。从机制上讲，这种作用是通过抑制特定免疫细胞（如3型天然淋巴细胞（ILC3s）和Th17细胞）中的RORγt介导的，而不是通过抑制肿瘤细胞中的RORγ。这减少了促炎细胞因子的产生，包括白细胞介素-17A（IL-17A）、IL-17F和IL-22，并降低了肿瘤细胞的增殖。此外，TCGA分析显示，RORC表达升高与肺腺癌（LUAD）患者的肿瘤微环境（TME）改变和预后较差有关。这些发现突出了靶向RORγt以减少促肿瘤炎症的治疗潜力，并提出了一种LC治疗策略。
