IKZF4/NONO-RAB11FIP3 axis promotes immune evasion in gastric cancer via facilitating PD-L1 endosome recycling.

Abstract

As an immune checkpoint protein expressed by diverse cancer cells, programmed death ligand 1 (PD-L1) facilitates immune evasion by interacting with programmed cell death-1 (PD-1) on T cells. Despite the clinical benefits observed in various cancer types, strategies targeting PD-1/PD-L1 have demonstrated limited efficacy in gastric cancer (GC). Furthermore, the regulation of PD-L1, especially at post-translational modification levels, remains largely unknown. Therefore, it is crucial to elucidate the mechanisms governing PD-L1 expression to enhance anti-tumor immunity. In this study, we have identified that IKAROS family zinc finger 4 (IKZF4) and Non-POU domain-containing octamer-binding (NONO) synergistically regulate and enhance the expression of RAB11 family-interacting protein 3 (RAB11FIP3) in GC. The IKZF4/NONO-RAB11FIP3 axis facilitates the endosomal recycling of PD-L1, particularly on the cell membrane of GC cells. Moreover, overexpression of RAB11FIP3 mitigates the hypo-expression of PD-L1 protein resulting from IKZF4 or NONO deletion. Functionally, the silencing of RAB11FIP3 or IKZF4 promotes T cell proliferation, and enhances T-cell cytotoxicity towards GC cells in vitro, which further inhibits tumor immune evasion in mice via increasing the infiltration of CD8+ T cells into the tumor microenvironment (TME) to suppress GC progression. Our study suggests that the IKZF4/NONO-RAB11FIP3 axis promotes immune evasion by facilitating PD-L1 endosome recycling, thus presenting a potential therapeutic target for GC treatment.

• Authors: Nuoqing Weng, Chuzhou Zhou, Yuhang Zhou, Yanping Zhong, Zhe Jia, Xionghui Rao, Huaiyu Qiu, Guangyan Zeng, Xinghan Jin, Jianbao Zhang, Zhehong Zhuang, Zhihao Liang, Yuan Deng, Qinghai Li, Shasha Yang, Huixing Luo, Huiyun Wang, Xiaobin Wu
• Journal: Cancer letters (Cancer Lett) Vol. 584 Pg. 216618 (Mar 01 2024) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 38211652 (Publication Type: Journal Article)
• Copyright: Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• B7-H1 Antigen
• Programmed Cell Death 1 Receptor
• Transcription Factors
• RAB11FIP3 protein, human
• NONO protein, human
• IKZF4 protein, human
• CD274 protein, human

Topics

• Animals
• Mice
• B7-H1 Antigen
• CD8-Positive T-Lymphocytes
• Endosomes (metabolism)
• Immune Evasion
• Programmed Cell Death 1 Receptor (metabolism)
• Stomach Neoplasms (metabolism)
• Transcription Factors (metabolism)
• Tumor Microenvironment
• Humans