The Complement System: A Potential Therapeutic Target in Liver Cancer

Yuan, Meng; Liu, Li; Wang, Chenlin; Zhang, Yan; Zhang, Jiandong

doi:10.3390/life12101532

Cited by 5 publications

(5 citation statements)

References 119 publications

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“…Therefore, novel therapeutics are still needed. Immunotherapy with directed complement activation is a promising approach 17 . The activation of the classical pathway of complement contributes to the therapeutic efficacy of Rituximab 18–20 .…”

Section: Discussionmentioning

confidence: 99%

Complement-Activating Multimeric Immunotherapeutic Complexes for HER2-breast cancer immunotherapy

Seguin-Devaux,

Brandus,

Plesseria

et al. 2024

Preprint

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BackgroundDirecting selective complement activation towards tumor cells is an attractive strategy to promote their elimination. We have generated Complement-activating Multimeric immunotherapeutic compleXes (CoMiX) that selectively stimulate the alternative pathway using Factor H Related protein 4 (FHR4) or the classical complement pathways using triple Fc dimers on HER2-expressing tumor cells.MethodsWe used the C4bp C-terminal-α-/β-chain multimerising scaffolds to generate CoMiX-FHR4 and CoMiX-Fc with 2 different VHH anti-HER2, VHH(T) and VHH(P), recognising trastuzumab-or pertuzumab-competing HER2 epitopes, respectively: FHR4/VHH(T), FHR4/VHH(P), VHH(T)/Fc, VHH(P)/Fc. The different CoMiX were comparedin vitrofor C3b and C5b9 depositions, complement-dependent cytotoxicity, and their ability to activate NK cells and phagocytosis by macrophages using one-way ANOVA and post-hoc Tukey’s tests. We further explored their therapeutic efficacyin vivoon human BT474 breast cancer xenografts established in NUDE mice, when used individually or in combination, as compared to trastuzumab or pertuzumab.ResultsFHR4/VHH(T) and FHR4/VHH(P) led to the highest C3b and C5b9 depositions and CDC, both individually and in combinations on BT474 tumor cells (p< 0.0001) surpassing the very low complement activating capacity of trastuzumab and pertuzumab. CoMiX-Fc showed NK cell activation and complement-mediated BT474 phagocytosis by M2 macrophages. In the xenograft model, CoMiX-FHR4 molecules reduced the tumor volume by a factor of 7.33 compared to the PBS control. VHH(T)/Fc had no effect on tumor growth, while VHH(P)/Fc led to a 2.75-times tumor volume reduction that was higher than pertuzumab (p< 0.01). Trastuzumab and its combination with pertuzumab remained the most potent regimen, alone or in combination, to completely inhibit tumor growth. CoMiX-FHR4, CoMiX-Fc and C3b deposition were visualized as soon as one hour after injection resulting in a massive homogeneous complement deposit 6 hours after injection. Interestingly, CoMiX-FHR4 significantly reduced the growth of trastuzumab-resistant cancer cells in contrast to trastuzumab and induced a large NK cell infiltration into the tumor.ConclusionsCoMiX-FHR4 and CoMiX VHH(P)/Fc significantly inhibit tumor growth through complement activation, NK cells infiltration, and phagocytosis by macrophages. CoMiX-FHR4 proteins delay xenograft growth of BT474 cells resistant to trastuzumab and could thus be an attractive approach when resistance to antibody emerges.Key messagesWhat is already known on this topicComplement activation represents a substantial part of the overall biological activity of few therapeutic antibodies used in cancer immunotherapy. Factor H-related protein 4 can activate complement by serving as a platform for the assembly of alternative pathway C3 convertase by competing with factor H for C3b binding. We previously showed that multimeric recombinant proteins displaying the FHR4 complement effector moiety and a nanobody anti-HER2 targeting moiety selectively direct the activation of the complement alternative pathway on HER2-expressing tumor cells, leading to subsequent cell destruction through direct cell lysis or through the activation of host effector cells.What this study addsWe used in the current work a novel complement-directed tumor cell distruction strategyin vivo. We showed that CoMiX-FHR4 and CoMiX-Fc (based on triple Fc dimers), targeting HER2-positive breast tumor cells, inhibit tumor growth in a model of BT474 xenograft in NUDE mice by stimulating complement activation, BT474 death, NK cell activation, and phagocytosis of tumor cells by macrophages. CoMiX-FHR4 remain efficient in xenografts of BT474 cells resistant to trastuzumab.How this study might affect research, practice or policyWe demonstrate for the first time that directed complement activation on tumor cells is an alternative to therapeutic antibodies which is particularly promising when resistance to standard-of-care treatment occurs.

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Section: Discussionmentioning

confidence: 99%

Complement-Activating Multimeric Immunotherapeutic Complexes for HER2-breast cancer immunotherapy

Seguin-Devaux,

Brandus,

Plesseria

et al. 2024

Preprint

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“…Complement and coagulation cascades (Figure 8 D) act as the connection between innate and adaptive immunity. Recent studies report that complement system can influence LIHC progression by regulating the tumor microenvironment, tumor cells, and cancer stem cells 41 . As an important signaling molecules, peroxisome proliferator-activated receptors (PPARs) are involved in many physiological processes (Figure 8 D), and can improve non-alcoholic fatty liver disease by regulating lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Vesicle-mediated transport-related genes predict the prognosis and immune microenvironment in hepatocellular carcinoma

Ye,

Wang,

Yuan

et al. 2024

J. Cancer

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Background : Liver hepatocellular carcinoma (LIHC) is one of the leading causes of cancer-related death. The prognostic outcomes of advanced LIHC patients are poor. Hence, reliable prognostic biomarkers for LIHC are urgently needed. Methods : Data for vesicle-mediated transport-related genes (VMTRGs) were profiled from 338 LIHC and 50 normal tissue samples downloaded from The Cancer Genome Atlas (TCGA). Univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were performed to construct and optimize the prognostic risk model. Five GEO datasets were used to validate the risk model. The roles of the differentially expressed genes (DEGs) were investigated via Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses. Differences in immune cell infiltration between the high- and low-risk groups were evaluated using five algorithms. The “pRRophetic” was used to calculate the anticancer drug sensitivity of the two groups. Transwell and wound healing assays were performed to assess the role of GDP dissociation inhibitor 2 (GDI2) on LIHC cells. Results : A total of 166 prognosis-associated VMTRGs were identified, and VMTRGs-based risk model was constructed for the prognosis of LIHC patients. Four VMTRGs (GDI2, DYNC1LI1, KIF2C, and RAB32) constitute the principal components of the risk model associated with the clinical outcomes of LIHC. Tumor stage and risk score were extracted as the main prognostic indicators for LIHC patients. The VMTRGs-based risk model was significantly associated with immune responses and high expression of immune checkpoint molecules. High-risk patients were less sensitive to most chemotherapeutic drugs but benefited from immunotherapies. In vitro cellular assays revealed that GDI2 significantly promoted the growth and migration of LIHC cells. Conclusions : A VMTRGs-based risk model was constructed to predict the prognosis of LIHC patients effectively. This risk model was closely associated with the immune infiltration microenvironment. The four key VMTRGs are powerful prognostic biomarkers and therapeutic targets for LIHC.

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“… 35 In cancers including HCC, release of complement mediators such as C2 and C3 has been linked to macrophage polarisation and TIL functional reprogramming, raising questions as to their potential role as a therapeutic target for cancer immunotherapy. 36 …”

Section: Discussionmentioning

confidence: 99%

Integrated phenotyping of the anti-cancer immune response in HIV-associated hepatocellular carcinoma

Pinato¹,

Kaneko²,

D’Alessio³

et al. 2023

JHEP Reports

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The Complement System: A Potential Therapeutic Target in Liver Cancer

Cited by 5 publications

References 119 publications

Complement-Activating Multimeric Immunotherapeutic Complexes for HER2-breast cancer immunotherapy

Complement-Activating Multimeric Immunotherapeutic Complexes for HER2-breast cancer immunotherapy

Vesicle-mediated transport-related genes predict the prognosis and immune microenvironment in hepatocellular carcinoma

Integrated phenotyping of the anti-cancer immune response in HIV-associated hepatocellular carcinoma

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