RORγt Inhibition Reduces Protumor Inflammation and Decreases Tumor Growth in Experimental Models of Lung Cancer

초록

The retinoic acid receptor-related orphan receptor C (RORC) gene encodes two isoforms, ROR gamma and ROR gamma t, which function as transcription factors in different cell types. ROR gamma t is expressed in specific immune cells involved in inflammatory responses, whereas ROR gamma is found in parenchymal cells, in which it participates in metabolism and circadian rhythm regulation. Although the roles of ROR gamma t in CD4+ Th17 lymphocytes and ROR gamma in certain cancer cell types are increasingly recognized, their relative contributions to lung cancer development remain unclear. In this study, we investigated the roles of RORC, ROR gamma, and ROR gamma t in lung cancer using mouse models and human data from The Cancer Genome Atlas. We evaluated the effects of Rorc gene deletion and ROR gamma/gamma t pharmacologic inhibition in cancer and immune cells in vitro and in vivo. Pharmacologic blockade of ROR gamma/gamma t with digoxin significantly reduced lung cancer development in two mouse models: a KrasG12D-driven genetic model and a urethane-induced chemical model. Mechanistically, this effect was mediated by inhibition of ROR gamma t in specific immune cells, such as type 3 innate lymphoid cells and Th17 cells, rather than by inhibiting ROR gamma in tumor cells. This reduced the production of proinflammatory cytokines, including IL17A, IL17F, and IL22, and decreased tumor cell proliferation. Additionally, The Cancer Genome Atlas analysis revealed that elevated RORC expression is associated with an altered tumor microenvironment and poorer prognosis in patients with lung adenocarcinoma. These findings highlight the therapeutic potential of targeting ROR gamma t to reduce protumor inflammation and propose a strategy for lung cancer treatment.

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