Details

Autor(en) / Beteiligte

• Wei, Cheng-Hsin
• Huang, Lu
• Kreh, Blair
• Liu, Xiuxia
• Tyutyunyk-Massey, Liliya
• Kawakami, Masanori
• Chen, Zibo
• Shi, Mi
• Kozlov, Serguei
• Chan, King C
• Andresson, Thorkell
• Carrington, Mary
• Vuligonda, Vidyasagar
• Sanders, Martin E
• Horowitz, Amir
• Hwu, Patrick
• Peng, Weiyi
• Dmitrovsky, Ethan
• Liu, Xi

Titel

A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment

Ist Teil von

• Scientific reports, 2023-09, Vol.13 (1), p.14907-14907, Article 14907

Ort / Verlag

London: Nature Publishing Group

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Abstract 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.