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

• Published in: Scientific reports 2023-09, Vol.13 (1), p.14907-14907, Article 14907
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 631/67/1612; 631/67/580; 692/308/153; 692/308/2778; Agonists; CD38 antigen; CD4 antigen; CD8 antigen; Cell differentiation; Combined treatment; Humanities and Social Sciences; Immune checkpoint inhibitors; Immunodeficiency; Interleukin 13; Interleukin 5; Lung cancer; Lymphocytes; Lymphocytes T; multidisciplinary; PD-L1 protein; Pharmacokinetics; Retinoic acid; Retinoic acid receptors; Science; Science (multidisciplinary); Statistical analysis; Stroma; Tumor microenvironment; Tumorigenicity; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-41690-5

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.