CD147-K148me2-Driven Tumor Cell-Macrophage Crosstalk Provokes NSCLC Immunosuppression via the CCL5/CCR5 Axis

Ke Wang ^1,2, Xiaohong Chen ^1,2, Peng Lin ^1,2

⁰Department of Cell Biology of National Translational Science Center for Molecular Medicine and Department of Clinical Immunology of Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.

Advanced Science (weinheim, Baden-Wurttemberg, Germany) +

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June 14, 2024

View abstract on PubMed

Summary

Di-methylation of cluster of differentiation 147 (CD147) at Lys148 promotes non-small cell lung cancer (NSCLC) progression by enhancing immunosuppression. Targeting this modification with antibody 12C8 may offer a novel NSCLC therapy.

Area Of Science

Oncology
Immunology
Biochemistry

Background

Immunosuppression is a key factor in non-small cell lung cancer (NSCLC) progression.
Cluster of differentiation 147 (CD147) is implicated in NSCLC immunosuppression, but its post-translational modifications remain understudied.
The specific role of CD147 di-methylation in the tumor microenvironment (TME) is unclear.

Purpose Of The Study

To investigate the role of CD147 di-methylation in NSCLC immunosuppression and tumor progression.
To identify the methyltransferase responsible for CD147 di-methylation and elucidate the underlying mechanisms.
To explore the therapeutic potential of targeting CD147 di-methylation in NSCLC.

Main Methods

Identification and validation of CD147 di-methylation at Lys148 (CD147-K148me2) as a post-translational modification in NSCLC.
Enzymatic assays to confirm NSD2 as the methyltransferase catalyzing CD147-K148me2.
Analysis of CD147-K148me2's impact on cyclophilin A interaction, CCL5 transcription, and M2-like tumor-associated macrophage (TAM) infiltration.
Inhibition studies using the targeted antibody 12C8.

Main Results

CD147-K148me2 is a common PTM in NSCLC associated with poor survival, particularly in advanced stages.
NSCLC progression and immunosuppressive TME are reestablished by CD147-K148me2.
CD147-K148me2 enhances CyPA interaction, upregulates CCL5 via p38-ZBTB32 signaling, and promotes M2-like TAM infiltration through the CCL5/CCR5 axis.
The antibody 12C8 effectively inhibits CD147-K148me2-mediated immunosuppression.

Conclusions

CD147-K148me2 is a critical driver of NSCLC immunosuppression and progression.
The CD147-K148me2-CCL5-TAM axis represents a novel mechanism of tumor-immune evasion in NSCLC.
Targeting CD147-K148me2 with specific antibodies like 12C8 offers a promising therapeutic strategy for NSCLC.

Keywords:

CCL5 CD147‐K148me2 NSD2 non‐small cell lung cancer tumor‐associated macrophages