Complement receptor <scp>C5aR1</scp> blockade reprograms tumor‐associated macrophages and synergizes with <scp>anti‐PD</scp>‐1 therapy in gastric cancer

Zhang, Puran; Gu, Yun; Wang, Jieti; Lv, Kunpeng; Lin, Chao; Zhang, Heng; Li, He; He, Hongyong; Li, Ruochen; Líu, Hao; Xu, Jiejie

doi:10.1002/ijc.34474

Cited by 8 publications

(6 citation statements)

References 51 publications

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“…A genetic reduction in the SRC kinase HCK prevents STAT3-based GC growth [46] . Blockade of the complement receptor C5AR1 enables tumor-associated macrophages to be reprogrammed and reinvigorated CD8 + T-cell-mediated antitumor immunity, thereby synergizing with anti-PD-1 therapy for GC tumor eradication [47] . After further verification of C5AR1, we found that specific suppression of C5AR1 prevented GC growth and provoked intracellular ROS generation.…”

Section: Discussionmentioning

confidence: 99%

Identification of neutrophil extracellular trap-driven gastric cancer heterogeneity and C5AR1 as a therapeutic target

Zhao,

Li,

et al. 2024

ABBS

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Neutrophil extracellular traps (NETs) are implicated in gastric cancer (GC) growth, metastatic dissemination, cancer-associated thrombosis, etc . This work is conducted to elucidate the heterogeneity of NETs in GC. The transcriptome heterogeneity of NETs is investigated in TCGA-STAD via a consensus clustering algorithm, with subsequent external verification in the GSE88433 and GSE88437 cohorts. Clinical and molecular traits, the immune microenvironment, and drug response are characterized in the identified NET-based clusters. Based upon the feature genes of NETs, a classifier is built for estimating NET-based clusters via machine learning. Multiple experiments are utilized to verify the expressions and implications of the feature genes in GC. A novel NET-based classification system is proposed for reflecting the heterogeneity of NETs in GC. Two NET-based clusters have unique and heterogeneous clinical and molecular features, immune microenvironments, and responses to targeted therapy and immunotherapy. A logistic regression model reliably differentiates the NET-based clusters. The feature genes C5AR1 , CSF1R , CSF2RB , CYBB , HCK , ITGB2 , LILRB2 , MNDA , MPEG1 , PLEK , SRGN , and STAB1 are proven to be aberrantly expressed in GC cells. Specific knockdown of C5AR1 effectively hinders GC cell growth and elicits intracellular ROS accumulation. In addition, its suppression suppresses the aggressiveness and EMT phenotype of GC cells. In all, NETs are the main contributors to intratumoral heterogeneity and differential drug sensitivity in GC, and C5AR1 has been shown to trigger GC growth and metastatic spread. These findings collectively provide a theoretical basis for the use of anti-NETs in GC treatment.

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Section: Discussionmentioning

confidence: 99%

Identification of neutrophil extracellular trap-driven gastric cancer heterogeneity and C5AR1 as a therapeutic target

Zhao,

Li,

et al. 2024

ABBS

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“…reported that high expression of C5aR1‐positive TAMs not only forecasted the poor OS (459 samples) for GC patients but also predicted worse response to 5‐FU for advanced GC patients (342 samples). 158 Similarly, Liu et al. found that high infiltration of Dectin‐1‐positive TAMs usually predicted worse OS and DFS of GC patients (451 samples).…”

Section: The Relationship Between Tams and The Prognosis Of Patients ...mentioning

confidence: 94%

“…Zhang et al. reported that high expression of C5aR1‐positive TAMs not only forecasted the poor OS (459 samples) for GC patients but also predicted worse response to 5‐FU for advanced GC patients (342 samples) 158 . Similarly, Liu et al.…”

Section: The Relationship Between Tams and The Prognosis Of Patients ...mentioning

confidence: 95%

“…demonstrated that targeting CD47 was a potent immunotherapy by enhancing phagocytosis and IFN‐β secretions of TAMs through activating cGAS‐STING signalling in Epstein–Barr virus‐associated GC 157 . When targeting SIGLEC10, 131 C5aR1 158 and Dectin‐1 159 mainly expressed on TAMs not only reprogrammed TAMs but also boosted the tumour‐killing function of CD8 + T cells and the efficacy of PD‐1 inhibitors. Melatonin, one of the autocrine hormones in the human body, has been reported to reduce the PD‐L1 expression in TAMs and enhance the function of CD8 + T cells by affecting the EVs secretions of GC cells 160 .…”

Section: Applications Of Tams In Gc Treatmentmentioning

confidence: 99%

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Tumour‐associated macrophages in gastric cancer: From function and mechanism to application

Li,

Sun,

Zeng

et al. 2023

Clinical & Translational Med

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BackgroundGastric cancer (GC) is a malignant tumour, with high morbidity and mortality rates worldwide. The occurrence and development of GC is a complex process involving genetic changes in tumour cells and the influence of the surrounding tumour microenvironment (TME). Accumulative evidence shows that tumour‐associated macrophages (TAMs) play a vital role in GC, acting as plentiful and active infiltrating inflammatory cells in the TME.Main bodyIn this review, the different functions and mechanisms of TAMs in GC progression, including the conversion of phenotypic subtypes; promotion of tumour proliferation, invasion and migration; induction of chemoresistance; promotion of angiogenesis; modulation of immunosuppression; reprogramming of metabolism; and interaction with the microbial community are summarised. Although the role of TAMs in GC remains controversial in clinical settings, clarifying their significance in the treatment selection and prognostic prediction of GC could support optimising TAM‐centred clinicaltherapy.ConclusionIn summary, we reviewed the the phenotypic polarisation, function and molecular mechanism of TAMs and their potential applications in the treatment selection and prognostic prediction of GC.

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“…CD206 blockade also enhanced antitumor immune response in syngeneic models and the mouse pancreatic tumor model ( 168 ). Blockade of complement receptor C5aR1 also reprogramed tumor-associated macrophages ( 169 ).…”

Section: Tumor-associated Macrophages As a Target Against Tumormentioning

confidence: 99%

Novel tumor-associated macrophage populations and subpopulations by single cell RNA sequencing

Wang,

Zhu,

et al. 2024

Front. Immunol.

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Tumor-associated macrophages (TAMs) are present in almost all solid tumor tissues. 16They play critical roles in immune regulation, tumor angiogenesis, tumor stem cell activation, tumor invasion and metastasis, and resistance to therapy. However, it is unclear how TAMs perform these functions. With the application of single-cell RNA sequencing (scRNA-seq), it has become possible to identify TAM subpopulations associated with distinct functions. In this review, we discuss four novel TAM subpopulations in distinct solid tumors based on core gene signatures by scRNA-seq, including FCN1+, SPP1+, C1Q+ and CCL18+ TAMs. Functional enrichment and gene expression in scRNA-seq data from different solid tumor tissues found that FCN1+ TAMs may induce inflammation; SPP1+ TAMs are potentially involved in metastasis, angiogenesis, and cancer cell stem cell activation, whereas C1Q+ TAMs participate in immune regulation and suppression; And CCL18+ cells are terminal immunosuppressive macrophages that not only have a stronger immunosuppressive function but also enhance tumor metastasis. SPP1+ and C1Q+ TAM subpopulations can be further divided into distinct populations with different functions. Meanwhile, we will also present emerging evidence highlighting the separating macrophage subpopulations associated with distinct functions. However, there exist the potential disconnects between cell types and subpopulations identified by scRNA-seq and their actual function.

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Complement receptor C5aR1 blockade reprograms tumor‐associated macrophages and synergizes with anti‐PD‐1 therapy in gastric cancer

Cited by 8 publications

References 51 publications

Identification of neutrophil extracellular trap-driven gastric cancer heterogeneity and C5AR1 as a therapeutic target

Identification of neutrophil extracellular trap-driven gastric cancer heterogeneity and C5AR1 as a therapeutic target

Tumour‐associated macrophages in gastric cancer: From function and mechanism to application

Novel tumor-associated macrophage populations and subpopulations by single cell RNA sequencing

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