Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity.

Abstract

PURPOSE:

Multiple negative regulators restrict the ability of T cells to attack tumors. This work demonstrates the role of PI3K-interacting protein 1 (Pik3ip1) in restraining T-cell responses and antitumor immunity.

EXPERIMENTAL DESIGN:

An anti-Pik3ip1 mAb was generated to identify the Pik3ip1 expression pattern of hematopoietic cells. Pik3ip1 -/- mice and a Pik3ip1 fusion protein were generated to investigate the effect of Pik3ip1 on T-cell-mediated antitumor immunity in MC38 and B16-F10 tumor models. Immunoblotting and confocal microscopy were used to identify inhibitory effects of Pik3ip1 on T-cell receptor (TCR) signaling. Pik3ip1 expression was quantified, and its impact on T-cell function in human tumors was measured.

RESULTS:

We demonstrated that Pik3ip1 was predominantly expressed on T cells and served as an essential rheostat for T-cell-mediated immunity. A Pik3ip1 genetic deficiency led to enhanced T-cell responsiveness upon immunization with a neoantigen. Pik3ip1 -/- mice exhibited a marked increase in antitumor immunity and were resistant to tumor growth. Furthermore, Pik3ip1 extracellular domain fusion protein enhanced MC38 tumor growth was observed. Mechanistically, we found that Pik3ip1 inhibited TCR signaling by mediating the degradation of SLP76 through Pik3ip1 oligomerization via its extracellular region. Consistent with the results from the mouse models, PIK3IP1 expression correlated with T-cell dysfunction in human tumors.

CONCLUSIONS:

Our data reveal a critical role for Pik3ip1 as a novel inhibitory immune regulator of T-cell responses and provide a potential molecular target for cancer immunotherapy.

• Authors: Yichen Chen, Jun Wang, Xi Wang, Xinye Li, Jingjing Song, Juan Fang, Xiangqi Liu, Tao Liu, Dikan Wang, Qunxing Li, Shuqiong Wen, Da Ma, Juan Xia, Liqun Luo, Song Guo Zheng, Jun Cui, Gucheng Zeng, Lieping Chen, Bin Cheng, Zhi Wang
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 20 Pg. 6180-6194 (10 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 31350312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Immunological
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• PIK3IP1 protein, human
• Pik3ip1 protein, mouse
• Recombinant Fusion Proteins

Topics

• Animals
• Antineoplastic Agents, Immunological (pharmacology, therapeutic use)
• Cell Line, Tumor (transplantation)
• Disease Models, Animal
• Humans
• Immunity, Cellular
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, genetics, immunology, metabolism)
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism)
• Membrane Proteins (antagonists & inhibitors, genetics, immunology, metabolism)
• Mice
• Mice, Knockout
• Neoplasms (blood, drug therapy, immunology, pathology)
• Primary Cell Culture
• Recombinant Fusion Proteins (genetics, immunology)
• T-Lymphocytes (immunology, metabolism)
• Tumor Microenvironment (drug effects, immunology)