Dataset Information

Soluble programmed death ligand-1-induced immunosuppressive effects on chimeric antigen receptor-natural killer cells targeting Glypican-3 in hepatocellular carcinoma.

ABSTRACT: Although the pre-clinical study of chimeric antigen receptor (CAR)-natural killer (NK) cell was effective against various tumours, immunosuppression mediated by tumour microenvironment hampers their application and several efforts have been explored to improve their effect in combating solid tumours. Glypican 3 (GPC3) is a promising target for hepatocellular carcinoma (HCC), and CAR-T cells targeting GPC3 have been tested in clinical trials. Based on an affinity-enhanced antibody (hYP7) targeting GPC3, we constructed GPC3-CAR-NK cells to explore their potential function in the treatment of HCC. We found that patients with HCC secreted high levels of soluble programmed death-ligand 1 (sPD-L1), which inhibits the function of CAR-NK cells targeting GPC3. In addition, we combined high-affinity sPD-L1 variant (L3C7c-Fc) with GPC3-CAR-NK cells to solve the problem of GPC3-CAR-NK inhibition. Our studies demonstrated that L3C7c-Fc could enhance the therapeutic effect of CAR-NK cells by reversing the suppression of sPD-L1, which provides the experimental evidence for the subsequent development of HCC immunotherapy strategies.

SUBMITTER: Chen L

PROVIDER: S-EPMC10712665 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Soluble programmed death ligand-1-induced immunosuppressive effects on chimeric antigen receptor-natural killer cells targeting Glypican-3 in hepatocellular carcinoma.

Chen Lin L Liu Siyuan S Adah Dickson D Sun Qingyang Q Liang Zhaoduan Z Ho Mitchell M Sun Beicheng B

Immunology 20230125 2

Although the pre-clinical study of chimeric antigen receptor (CAR)-natural killer (NK) cell was effective against various tumours, immunosuppression mediated by tumour microenvironment hampers their application and several efforts have been explored to improve their effect in combating solid tumours. Glypican 3 (GPC3) is a promising target for hepatocellular carcinoma (HCC), and CAR-T cells targeting GPC3 have been tested in clinical trials. Based on an affinity-enhanced antibody (hYP7) targetin ...[more]

PMID: 36640111

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Project description:Immunomodulatory drugs and monoclonal antibody-based immunotherapies have significantly improved the prognosis of the patients with multiple myeloma (MM) in the recent years. These new classes of reagents target malignant plasma cells (PCs) and further modulate the immune microenvironment, which prolongs anti-MM responses and may prevent tumor occurrence. Since MM remains an incurable cancer for most patients, there continues to be a need to identify new tumor target molecules and investigate alternative cellular approaches using gene therapeutic strategies and novel treatment mechanisms. Osteoclasts (OCs), as critical multi-nucleated large cells responsible for bone destruction in >80% MM patients, have become an attractive cellular target for the development of novel MM immunotherapies. In MM, OCs are induced and activated by malignant PCs in a reciprocal manner, leading to osteolytic bone disease commonly associated with this malignancy. Significantly, bidirectional interactions between OCs and MM cells create a positive feedback loop to promote MM cell progression, increase angiogenesis, and inhibit immune surveillance via both cell-cell contact and abnormal production of multiple cytokines/chemokines. Most recently, hyper-activated OCs have been associated with activation of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway, which impairs T cell proliferation and cytotoxicity against MM cells. Importantly, therapeutic anti-CD38 monoclonal antibodies and checkpoint inhibitors can alleviate OC-induced immune suppression. Furthermore, a proliferation-inducing ligand, abundantly secreted by OCs and OC precursors, significantly upregulates PD-L1 expression on MM cells, in addition to directly promoting MM cell proliferation and survival. Coupled with increased PD-L1 expression in other immune-suppressive cells, i.e., myeloid-derived suppressor cells and tumor-associated macrophages, these results strongly suggest that OCs contribute to the immunosuppressive MM BM microenvironment. Based on these findings and ongoing osteoimmunology studies, therapeutic interventions targeting OC number and function are under development to diminish both MM bone disease and related immune suppression. In this review, we discuss the classical and novel roles of OCs in the patho-immunology of MM. We also describe novel therapeutic strategies simultaneously targeting OCs and MM interactions, including PD-1/PD-L1 axis, to overcome the immune-suppressive microenvironment and improve patient outcome.

Project description:Background and aimsGlypican 3 (GPC3) is an oncofetal antigen involved in Wnt-dependent cell proliferation that is highly expressed in hepatocellular carcinoma (HCC). We investigated whether the functions of chimeric antigen receptors (CARs) that target GPC3 are affected by their antibody-binding properties.MethodsWe collected peripheral blood mononuclear cells from healthy donors and patients with HCC and used them to create CAR T cells, based on the humanized YP7 (hYP7) and HN3 antibodies, which have high affinities for the C-lobe and N-lobe of GPC3, respectively. NOD/SCID/IL-2Rgcnull (NSG) mice were given intraperitoneal injections of luciferase-expressing (Luc) Hep3B or HepG2 cells and after xenograft tumors formed, mice were given injections of saline or untransduced T cells (mock control), or CAR (HN3) T cells or CAR (hYP7) T cells. In other NOD/SCID/IL-2Rgcnull (NSG) mice, HepG2-Luc or Hep3B-Luc cells were injected into liver, and after orthotopic tumors formed, mice were given 1 injection of CAR (hYP7) T cells or CD19 CAR T cells (control). We developed droplet digital polymerase chain reaction and genome sequencing methods to analyze persistent CAR T cells in mice.ResultsInjections of CAR (hYP7) T cells eliminated tumors in 66% of mice by week 3, whereas CAR (HN3) T cells did not reduce tumor burden. Mice given CAR (hYP7) T cells remained tumor free after re-challenge with additional Hep3B cells. The CAR T cells induced perforin- and granzyme-mediated apoptosis and reduced levels of active β-catenin in HCC cells. Mice injected with CAR (hYP7) T cells had persistent expansion of T cells and subsets of polyfunctional CAR T cells via antigen-induced selection. These T cells were observed in the tumor microenvironment and spleen for up to 7 weeks after CAR T-cell administration. Integration sites in pre-infusion CAR (HN3) and CAR (hYP7) T cells were randomly distributed, whereas integration into NUPL1 was detected in 3.9% of CAR (hYP7) T cells 5 weeks after injection into tumor-bearing mice and 18.1% of CAR (hYP7) T cells at week 7. There was no common site of integration in CAR (HN3) or CD19 CAR T cells from tumor-bearing mice.ConclusionsIn mice with xenograft or orthoptic liver tumors, CAR (hYP7) T cells eliminate GPC3-positive HCC cells, possibly by inducing perforin- and granzyme-mediated apoptosis or reducing Wnt signaling in tumor cells. GPC3-targeted CAR T cells might be developed for treatment of patients with HCC.

Dataset Information

Soluble programmed death ligand-1-induced immunosuppressive effects on chimeric antigen receptor-natural killer cells targeting Glypican-3 in hepatocellular carcinoma.

Publications

Soluble programmed death ligand-1-induced immunosuppressive effects on chimeric antigen receptor-natural killer cells targeting Glypican-3 in hepatocellular carcinoma.

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