gC1qR: A New Target for Cancer Immunotherapy

Lei, Yanna; Li, Xiaoyü; Qin, Diyuan; Zhang, Yugu; Wang, Yongsheng

doi:10.3389/fimmu.2023.1095943

Cited by 8 publications

(4 citation statements)

References 98 publications

(119 reference statements)

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“…The novel interaction between gC1qR and HYAL2 unveiled another regulatory role of gC1qR: by acting on HA metabolism, gC1qR may control the key functions of HA in tumor progression and its involvement in most of the hallmarks of cancer, such as sustenance of proliferative signaling and tumorpromoting inflammation, evasion of apoptosis, induction of angiogenesis, promotion of invasion and metastases, deregulation of energy metabolism and evasion of the immune response (4). Our findings lend credence to recent literature which describe gC1qR as an immunoregulator of TME, determining progression and metastatic properties of cancer c e l l s , t h u s , b e c o m i n g a n o v e l p r o m i s i n g t a r g e t fo r immunotherapy (51). Peerschke et al already demonstrated that the blockage of gC1qR with the monoclonal antibody 60.11 caused a reduction in MPM tumor size due to apoptosis enhancement and decreased neovascularization (26).…”

Section: Discussionsupporting

confidence: 89%

Complement protein C1q stimulates hyaluronic acid degradation via gC1qR/HABP1/p32 in malignant pleural mesothelioma

et al. 2023

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Complement component C1q can act as a pro-tumorigenic factor in the tumor microenvironment (TME). The TME in malignant pleural mesothelioma (MPM) is rich in C1q and hyaluronic acid (HA), whose interaction enhances adhesion, migration and proliferation of malignant cells. HA-bound C1q is also capable of modulating HA synthesis. Thus, we investigated whether HA-C1q interaction would affect HA degradation, analyzing the main degradation enzymes, hyaluronidase (HYAL)1 and HYAL2, and a C1q receptor candidate. We first proceeded with the characterization of HYALs in MPM cells, especially HYAL2, since bioinformatics survival analysis revealed that higher HYAL2 mRNA levels have an unfavorable prognostic index in MPM patients. Interestingly, Real-Time quantitative PCR, flow cytometry and Western blot highlighted an upregulation of HYAL2 after seeding of primary MPM cells onto HA-bound C1q. In an attempt to unveil the receptors potentially involved in HA-C1q signaling, a striking co-localization between HYAL2 and globular C1q receptor/HABP1/p32 (gC1qR) was found by immunofluorescence, surface biotinylation and proximity ligation assays. RNA interference experiments revealed a potentially regulatory function exerted by gC1qR on HYAL2 expression, since C1QBP (gene for gC1qR) silencing unexpectedly caused HYAL2 downregulation. In addition, the functional blockage of gC1qR by a specific antibody hindered HA-C1q signaling and prevented HYAL2 upregulation. Thus, C1q-HA interplay is responsible for enhanced HYAL2 expression, suggesting an increased rate of HA catabolism and the release of pro-inflammatory and pro-tumorigenic HA fragments in the MPM TME. Our data support the notion of an overall tumor-promoting property of C1q. Moreover, the overlapping localization and physical interaction between HYAL2 and gC1qR suggests a potential regulatory effect of gC1qR within a putative HA-C1q macromolecular complex.

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Section: Discussionsupporting

confidence: 89%

Complement protein C1q stimulates hyaluronic acid degradation via gC1qR/HABP1/p32 in malignant pleural mesothelioma

et al. 2023

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“…Protein methylation plays a crucial role in tumor development and is involved in diverse biological processes, especially regulating protein-protein interactions that contribute to abnormal signal transduction and disease development. [30,31] CyPA and CD147 are regarded as essential ligand and receptor that activate multiple oncogenic signaling pathways, and agents that interfere with the interaction between CD147 and CyPA have the potential to inhibit tumor progression. [25] In our study, the dimethylation of CD147 at Lys148 had a potential influence on protein conformation, which increased the binding capacity of CyPA to CD147, and in turn activated the p38-ZBTB32 signaling, leading to increasing NSCLC cell-derived CCL5 secretion.…”

Section: Discussionmentioning

confidence: 99%

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

Wang,

Chen,

Lin

et al. 2024

Advanced Science

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Immunosuppression is a major hallmark of tumor progression in non‐small cell lung cancer (NSCLC). Cluster of differentiation 147 (CD147), an important pro‐tumorigenic factor, is closely linked to NSCLC immunosuppression. However, the role of CD147 di‐methylation in the immunosuppressive tumor microenvironment (TME) remains unclear. Here, di‐methylation of CD147 at Lys148 (CD147‐K148me2) is identified as a common post‐translational modification (PTM) in NSCLC that is significantly associated with unsatisfying survival outcomes among NSCLC sufferers, especially those in the advanced stages of the disease. The methyltransferase NSD2 catalyzes CD147 to generate CD147‐K148me2. Further analysis demonstrates that CD147‐K148me2 reestablishes the immunosuppressive TME and promotes NSCLC progression. Mechanistically, this modification promotes the interaction between cyclophilin A (CyPA) and CD147, and in turn, increases CCL5 gene transcription by activating p38‐ZBTB32 signaling, leading to increased NSCLC cell‐derived CCL5 secretion. Subsequently, CD147‐K148me2‐mediated CCL5 upregulation facilitates M2‐like tumor‐associated macrophage (TAM) infiltration in NSCLC tissues via CCL5/CCR5 axis‐dependent intercellular crosstalk between tumor cells and macrophages, which is inhibited by blocking CD147‐K148me2 with the targeted antibody 12C8. Overall, this study reveals the role of CD147‐K148me2‐driven intercellular crosstalk in the development of NSCLC immunosuppression, and provides a potential interventional strategy for PTM‐targeted NSCLC therapy.

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“…Previous experiments have shown that targeting gC1qR-expressing cells with C1q induces an antiproliferative response ( 38 ). Because high gC1qR expression by most cancer cells is associated with poor survival, gC1qR has become a potential prime target for the development of anti-cancer therapy ( 43 , 44 ). Indeed, we are very much aware that targeting such a ubiquitously expressed, multifunctional, and multicompartmental molecule, would theoretically present an undesirable collateral risk since it has the potential to lead to deleterious off-target blockade of important biological functions.…”

Section: Preliminary Proof-of-concept Studies In Animal Modelsmentioning

confidence: 99%

The C1q and gC1qR axis as a novel checkpoint inhibitor in cancer

Ghebrehiwet,

Zaniewski,

Fernandez

et al. 2024

Front. Immunol.

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Understanding at the molecular level of the cell biology of tumors has led to significant treatment advances in the past. Despite such advances however, development of therapy resistance and tumor recurrence are still unresolved major challenges. This therefore underscores the need to identify novel tumor targets and develop corresponding therapies to supplement existing biologic and cytotoxic approaches so that a deeper and more sustained treatment responses could be achieved. The complement system is emerging as a potential novel target for cancer therapy. Data accumulated to date show that complement proteins, and in particular C1q and its receptors cC1qR/CR and gC1qR/p33/HABP1, are overexpressed in most cancer cells and together are involved not only in shaping the inflammatory tumor microenvironment, but also in the regulation of angiogenesis, metastasis, and cell proliferation. In addition to the soluble form of C1q that is found in plasma, the C1q molecule is also found anchored on the cell membrane of monocytes, macrophages, dendritic cells, and cancer cells, via a 22aa long leader peptide found only in the A-chain. This orientation leaves its 6 globular heads exposed outwardly and thus available for high affinity binding to a wide range of molecular ligands that enhance tumor cell survival, migration, and proliferation. Similarly, the gC1qR molecule is not only overexpressed in most cancer types but is also released into the microenvironment where it has been shown to be associated with cancer cell proliferation and metastasis by activation of the complement and kinin systems. Co-culture of either T cells or cancer cells with purified C1q or anti-gC1qR has been shown to induce an anti-proliferative response. It is therefore postulated that in the tumor microenvironment, the interaction between C1q expressing cancer cells and gC1qR bearing cytotoxic T cells results in T cell suppression in a manner akin to the PD-L1 and PD-1 interaction.

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gC1qR: A New Target for Cancer Immunotherapy

Cited by 8 publications

References 98 publications

Complement protein C1q stimulates hyaluronic acid degradation via gC1qR/HABP1/p32 in malignant pleural mesothelioma

Complement protein C1q stimulates hyaluronic acid degradation via gC1qR/HABP1/p32 in malignant pleural mesothelioma

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

The C1q and gC1qR axis as a novel checkpoint inhibitor in cancer

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