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Updated: Jan 15, 2026
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Anticancer immune responses are hindered by cis interaction of inhibitory checkpoint SIRPα
Zhenghai Tang1,2,3, Ming-Chao Zhong1, Jin Qian1
1Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, Canada.
Abstract:
Signal regulatory protein α (SIRPα) is a macrophage inhibitory receptor that limits phagocytosis and antitumor activity by interacting in trans with CD47 on tumor cells. Here, we found that a component of SIRPα's inhibitory function occurred independently of CD47. Inhibition occurred because of interactions between SIRPα and CD18 (β2 integrin) in cis on the surface of macrophages, involving SIRPα amino acids distinct from those implicated in the SIRPα-CD47 interaction. This cis interaction prevented activation of CD18, which is necessary for phagocytosis. The combined blockade of SIRPα-CD18 and SIRPα-CD47 was essential for maximizing phagocytosis and suppression of tumor growth in vivo. Thus, inhibitory immune checkpoints such as SIRPα suppress cell activation through a mechanism targeting CD18 in cis, which occurs in addition to engagement by their inhibitory checkpoint ligands in trans. This dual mode of action should be considered when developing inhibitory checkpoint blockades for immunotherapy.
Insights
Signal regulatory protein α (SIRPα) limits antitumor activity via CD47. New research shows SIRPα also inhibits macrophages by binding CD18 in cis, blocking phagocytosis. Combined blockade enhances immunotherapy.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Signal regulatory protein α (SIRPα) is a macrophage receptor that inhibits phagocytosis and antitumor responses through interaction with CD47 on tumor cells.
- This interaction is a key target for cancer immunotherapies aiming to enhance macrophage-mediated tumor cell killing.
Purpose of the Study:
- To investigate the mechanisms by which SIRPα inhibits macrophage function, independent of CD47.
- To explore the role of cis-interactions of SIRPα in regulating macrophage activation and phagocytosis.
Main Methods:
- Utilized biochemical assays and cell-based experiments to study SIRPα interactions.
- Investigated the functional consequences of SIRPα-CD18 cis-interactions on macrophage activation and phagocytosis.
- Evaluated the efficacy of combined SIRPα-CD18 and SIRPα-CD47 blockade in preclinical cancer models.
Main Results:
- Identified a CD47-independent inhibitory function of SIRPα mediated by cis-interaction with CD18 (β2 integrin) on macrophages.
- Demonstrated that this cis-interaction prevents CD18 activation, a crucial step for phagocytosis.
- Showed that simultaneous blockade of SIRPα-CD18 and SIRPα-CD47 interactions is required to maximize phagocytosis and suppress tumor growth in vivo.
Conclusions:
- SIRPα employs a dual mechanism to suppress macrophage activation: trans-interaction with CD47 and cis-interaction with CD18.
- Targeting both the cis and trans inhibitory functions of SIRPα is essential for potent immunotherapy.
- This dual mode of action provides a new therapeutic strategy for enhancing cancer immunotherapy by overcoming macrophage inhibition.
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