B7-H3-targeted CAR-T cell therapy for solid tumors

Li, Guangfei; Wang, Haopeng; Wu, Haitao; Chen, Jian

doi:10.1080/08830185.2022.2102619

Cited by 14 publications

(10 citation statements)

References 83 publications

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“…PD‐1 ligands (PD‐L1) expressed by tumour cells bind PD‐1 on the surface of cytotoxic T cells, leading to T cell exhaustion [ 49 ]. B7‐H3, a co‐stimulatory molecule broadly overexpressed by multiple cancer cells, is considered as a promising therapeutic target for CAR‐T cells against GBM and other solid tumours [ 50 ]. Recent studies have reported that improved response to anti‐PD‐1 therapy is associated with higher PD‐L1 expression and TMB [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

An immune‐related multi‐omics analysis of dolichyl‐diphosphooligosaccharide protein glycosyltransferase in glioma: Prognostic value exploration and competitive endogenous RNA network identification

Liu,

Feng,

Liu

et al. 2023

IET Systems Biology

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Dolichyl‐diphosphooligosaccharide protein glycosyltransferase (DDOST) plays a pivotal role in the glycosylation of asparagine residues on nascent polypeptides. However, the biological role of DDOST in glioma remains unclear. The mRNA expression of DDOST in glioma was identified using TCGA, CGGA, GEO and Rembrandt datasets. Immunohistochemistry assay was conducted to examine the protein level of DDOST. Cox regression analysis, nomograms and calibration plots were used to evaluate the prognostic value of DDOST. The association between DDOST and immune cell infiltration was evaluated using CIBERSORT algorithm. Additionally, DNA methylation and ceRNA regulatory network of DDOST expression were investigated using the LinkedOmics and ENCORI databases. The authors found that DDOST was substantially expressed at the mRNA and protein levels. Functional enrichment analysis revealed close associations between DDOST and immune‐related pathways, as well as immune cell infiltration. In addition, DDOST exhibited synergistic effects with tumour mutational burden (TMB) and other immune checkpoints. For expression regulation mechanisms, DDOST had low DNA methylation levels in high‐grade gliomas and may be involved in multiple ceRNA networks in glioma. Thus, DDOST may serve as an unfavourable biomarker for gliomas. DNA methylation and ceRNA regulatory networks of DDOST expression were identified for the first time in this multi‐omics study.

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Section: Discussionmentioning

confidence: 99%

An immune‐related multi‐omics analysis of dolichyl‐diphosphooligosaccharide protein glycosyltransferase in glioma: Prognostic value exploration and competitive endogenous RNA network identification

Liu,

Feng,

Liu

et al. 2023

IET Systems Biology

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“…Our previous studies showed that B7-H3 (also known as CD276) is a tumorassociated antigen expressed on the surface of various cancer cell types and can be effectively targeted by B7-H3 specific CAR T cells [48,49]. To determine whether B7-H3 can also be used as a target antigen in human GBM, we first analyzed the gene expression profiles of glioma samples in The Cancer Genome Atlas (TCGA) [50 -52] and Chinese Glioma Genome Atlas (CGGA) databases [53].…”

Section: B7-h3/cd276 Is Highly Expressed In Gbmmentioning

confidence: 99%

Identification of genetic modifiers enhancing B7-H3-targeting CAR T cell therapy against glioblastoma through large-scale CRISPRi screening

Li,

Sun,

Zhang

et al. 2024

Preprint

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Background Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. Current treatment options are limited and often ineffective. CAR T cell therapy has shown success in treating hematologic malignancies, and there is growing interest in its potential application in solid tumors, including GBM. However, current CAR T therapy lacks clinical efficacy against GBM due to tumor-related resistance mechanisms and CAR T cell deficiencies. Therefore, there is a need to improve CAR T cell therapy efficacy in GBM. Methods We conducted large-scale CRISPR interference (CRISPRi) screens in GBM cell line U87 cells co-cultured with B7-H3 targeting CAR T cells to identify genetic modifiers that can enhance CAR T cell-mediated tumor killing. Flow cytometry-based tumor killing assay and CAR T cell activation assay were performed to validate screening hits. Bioinformatic analyses on bulk and single-cell RNA sequencing data and the TCGA database were employed to elucidate the mechanism underlying enhanced CAR T efficacy upon knocking down the selected screening hits in U87 cells. Results We established B7-H3 as a targetable antigen for CAR T therapy in GBM. Through large-scale CRISPRi screening, we discovered genetic modifiers in GBM cells, including ARPC4, PI4KA, ATP6V1A, UBA1, and NDUFV1, that regulated the efficacy of CAR T cell-mediated tumor killing. Furthermore, we discovered that TNFSF15 was upregulated in both ARPC4 and NDUFV1 knockdown GBM cells and revealed an immunostimulatory role of TNFSF15 in modulating tumor-CAR T interaction to enhance CAR T cell efficacy. Conclusions Our study highlights the power of CRISPR-based genetic screening in investigating tumor-CAR T interaction and identifies potential druggable targets in tumor cells that confer resistance to CAR T cell killing. Furthermore, we devised targeted strategies that synergize with CAR T therapy against GBM. These findings shed light on the development of novel combinatorial strategies for effective immunotherapy of GBM and other solid tumors.

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“…This non-selective tumor specificity is often the cause of high toxicity and adverse effects due to the cytotoxic reaction mediated by CAR-lymphocytes against normal tissues. So far, with a restricted expression in normal tissues and overexpression in many types of solid tumors, B7-H3 resulted a more promising therapeutic target compared to the others (76). DNAM-1 ligands PVR and Nectin-2 have been described to be absent or very scarcely expressed in normal tissue [proteinatlas.org and (73, 77)], so their targeting should hypothetically not be toxic; however, the differential expression of DNAM-1 ligands in cancer versus normal cells does not exclude a possible toxicity mediated by DNAM-1 chimeric receptor-engineered NK cells, which should be carefully explored by preclinical studies.…”

Section: Clinical Perspectivementioning

confidence: 99%

DNAM-1 chimeric receptor-engineered NK cells: a new frontier for CAR-NK cell-based immunotherapy

et al. 2023

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DNAM-1 is a major NK cell activating receptor and, together with NKG2D and NCRs, by binding specific ligands, strongly contributes to mediating the killing of tumor or virus-infected cells. DNAM-1 specifically recognizes PVR and Nectin-2 ligands that are expressed on some virus-infected cells and on a broad spectrum of tumor cells of both hematological and solid malignancies. So far, while NK cells engineered for different antigen chimeric receptors (CARs) or chimeric NKG2D receptor have been extensively tested in preclinical and clinical studies, the use of DNAM-1 chimeric receptor-engineered NK cells has been proposed only in our recent proof-of-concept study and deserves further development. The aim of this perspective study is to describe the rationale for using this novel tool as a new anti-cancer immunotherapy.

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B7-H3-targeted CAR-T cell therapy for solid tumors

Cited by 14 publications

References 83 publications

An immune‐related multi‐omics analysis of dolichyl‐diphosphooligosaccharide protein glycosyltransferase in glioma: Prognostic value exploration and competitive endogenous RNA network identification

An immune‐related multi‐omics analysis of dolichyl‐diphosphooligosaccharide protein glycosyltransferase in glioma: Prognostic value exploration and competitive endogenous RNA network identification

Identification of genetic modifiers enhancing B7-H3-targeting CAR T cell therapy against glioblastoma through large-scale CRISPRi screening

DNAM-1 chimeric receptor-engineered NK cells: a new frontier for CAR-NK cell-based immunotherapy

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