A novel oral TLR7 agonist orchestrates immune response and synergizes with PD-L1 blockade via type I IFN pathway in lung cancer

• Published in: International immunopharmacology Vol. 137; p. 112478
• Main Authors: Zuo, Xueying, Cheng, Qinpei, Wang, Zimu, Liu, Jiaxin, Lu, Wanjun, Wu, Guannan, Zhu, Suhua, Liu, Xin, Lv, Tangfeng, Song, Yong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 20.08.2024
• Subjects: Adaptive Immunity - drug effects; Administration, Oral; Animals; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Drug Synergism; Female; Humans; Immune checkpoint blockade; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunity, Innate - drug effects; Interferon Type I - metabolism; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Membrane Glycoproteins - agonists; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Signal Transduction - drug effects; T cell recruitment; TLR7; Toll-like receptor; Toll-Like Receptor 7 - agonists; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Type I interferon; TLR7; T cell recruitment; Immune checkpoint blockade; Type I interferon; Lung cancer; Toll-like receptor
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112478

[Display omitted] •Oral TLR7 agonist TQ-A3334 is well tolerated and effective in inhibiting tumor growth and priming immune responses in the LLC model.•TQ-A3334 can promote the infiltration of CD8+ T cells through the type I IFN pathway in TME.•TQ-A3334 can potentiate the anti-tumor performance of anti-PD-L1 therapy. Despite the groundbreaking impact of immune checkpoint blockade (ICB), response rates in non-small cell lung cancer remain modest, particularly in immune-excluded or immune-desert microenvironments. Toll-like receptor 7 (TLR7) emerges as a latent target bridging innate and adaptive immunity, offering a promising avenue for combination therapies to augment ICB efficacy. Here, we explored the anti-tumor activity of the novel oral TLR7 agonist TQ-A3334 and its potential to enhance anti-programmed death ligand 1 (PD-L1) therapy through a combination strategy in a syngeneic murine lung cancer model. Oral administration of TQ-A3334 significantly alleviated tumor burden in C57BL/6J mice, modulated by type I interferon (IFN), and exhibited low toxicity. This therapy elicited activation of both innate and adaptive immune cells in tumor tissue, particularly increasing the abundance of CD8+ TILs through type I IFN pathway and subsequent CXCL10 expression. In vitro examinations validated that IFN-α-stimulated tumor cells exhibited increased secretion of CXCL10, conducive to the promoted trafficking of CD8+ T cells. Furthermore, combining TQ-A3334 with anti-PD-L1 treatment exceeded tumor control, with a further increase in CD8+ TIL frequency compared to monotherapy. These findings suggest that TQ-A3334 can mobilize innate immunity and promote T cell recruitment into the tumor microenvironment; a combination of TQ-A3334 and anti-PD-L1 antibodies can intensify the sensitivity of tumors to anti-PD-L1 therapy, which demonstrates significant potential for treating poorly immune-infiltrated lung cancer.