Dataset Information

Anti-PD-1 antibody armored γδ T cells enhance anti-tumor efficacy in ovarian cancer.

ABSTRACT: γδ T cells have the unique ability to detect a wide range of tumors with low mutation burdens, making them attractive candidates for CAR-T-cell therapy. Unlike αβ T cells and other immune cells, γδ T cells are superior in MHC non-restriction, selective cell recruitment, and rapid activation. However, clinical trials have shown limited clinical benefits, and the adoptive transplantation of γδ T cells has often fallen short of expectations. We hypothesized that the limited effectiveness of γδ T cells in eradicating tumor cells may be attributed to the inhibitory tumor microenvironment induced by the suppressive PD-1/PD-L1 axis. Herein, we constructed novel armored γδ T cells capable of secreting humanized anti-PD-1 antibodies, referred to as "Lv-PD1-γδ T cells. Lv-PD1-γδ T cells showed improved proliferation and enhanced cytotoxicity against tumor cells, resulting in augmented therapeutic effects and survival benefits in ovarian tumor-bearing mice. These engineered cells demonstrated a prolonged in vivo survival of more than 29 days, without any potential for tumorigenicity in immunodeficient NOD/SCID/γ null mice. We also found that Lv-PD1-γδ T cells exhibited excellent tolerance and safety in humanized NOD/SCID/γ null mice. With attenuated or eliminated immunosuppression and maximized cytotoxicity efficacy by the local secretion of anti-PD1 antibodies in tumors, Lv-PD1-γδ T cells can serve as a promising "off-the-shelf" cell therapy against cancers.

SUBMITTER: Wang Y

PROVIDER: S-EPMC10587135 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Anti-PD-1 antibody armored γδ T cells enhance anti-tumor efficacy in ovarian cancer.

Wang Yue Y Han Jingyi J Wang Dongdong D Cai Menghua M Xu Yi Y Hu Yu Y Chen Hui H He Wei W Zhang Jianmin J

Signal transduction and targeted therapy 20231020 1

γδ T cells have the unique ability to detect a wide range of tumors with low mutation burdens, making them attractive candidates for CAR-T-cell therapy. Unlike αβ T cells and other immune cells, γδ T cells are superior in MHC non-restriction, selective cell recruitment, and rapid activation. However, clinical trials have shown limited clinical benefits, and the adoptive transplantation of γδ T cells has often fallen short of expectations. We hypothesized that the limited effectiveness of γδ T ce ...[more]

PMID: 37857598

Similar Datasets

Project description:Although programmed cell death-1/programmed death-ligand 1 (PD-L1) inhibitors show remarkable antitumor activity, a large portion of patients with cancer, even those with high PD-L1-expressing tumors, do not respond to their effects. Most PD-L1 inhibitors contain modified fragment crystallizable region (Fc) receptor binding sites to prevent antibody-dependent cellular cytotoxicity (ADCC) against PD-L1-expressing non-tumor cells. However, natural killer (NK) cells have specific antitumor activity in the presence of tumor-targeting antibody through ADCC, which could enhance NK cell-induced cytotoxicity. We evaluated the antitumor efficacy of ADCC via anti-PD-L1 monoclonal antibodies (mAbs) and NK cells against several PD-L1-positive cancer cell lines. Various cancer cell lines were used as target cell lines. Surface PD-L1 expression was analyzed by flow cytometry. IMC-001 and anti-hPD-L1-hIgG1 were tested as anti-PD-L1 mAbs with ADCC and atezolizumab as an anti-PD-L1 mAb without ADCC. NK cell cytotoxicity was measured by 51Cr-release assay and CD107a degranulation assay. Also, live cell imaging was performed to evaluate cytotoxicity in a single-cell level. NK-92-CD16 (CD16-transduced NK-92 cell line) and peripheral blood mononuclear cells from healthy donors, respectively, were used as an effector cell. FcγRIIIa (CD16a)-V158F genotyping was performed for healthy donors. We demonstrated that the cytotoxicity of NK-92-CD16 cells toward PD-L1-positive cancer cell lines was significantly enhanced in the presence of anti-PD-L1 mAb with ADCC. We also noted a significant increase in primary human NK cell cytotoxicity against PD-L1-positive human cancer cells when cocultured with anti-PD-L1 mAb with ADCC. Moreover, NK cells expressing a FCGR3A high-affinity genotype displayed higher anti-PD-L1 mAb-mediated ADCC lysis of tumor cells than donors with a low-affinity genotype. These results suggest that NK cells induce an ADCC response in combination with anti-PD-L1 mAbs, which helps promote ADCC antitumor activity against PD-L1-positive tumors. This study provides support for NK cell immunotherapy against high PD-L1-expressing tumors in combination with ADCC through anti-PD-L1 mAbs.

Project description:Radiotherapy (RT) triggers immunogenic cell death (ICD). L-ASNase, which catalyzes the conversion of asparagine (Asn), thereby depleting it, is used in the treatment of blood cancers. In previous work, we showed that CRT3LP and CRT4LP, PASylated L-ASNases conjugated to the calreticulin (CRT)-specific monobodies CRT3 and CRT4, increase the efficacy of ICD-inducing chemotherapy. Here, we assessed their efficacy in tumor-bearing mice treated with RT. Methods: Monobody binding was evaluated by in silico molecular docking analysis. The expression and cellular localization of ecto-CRT were assessed by confocal imaging and flow cytometry. The antitumor effect and the roles of CRT3LP and CRT4LP in irradiation (IR)-induced ICD in tumors were analyzed by ELISA, immunohistochemistry, and immune analysis methods. Results: Molecular docking analysis showed that CRT3 and CRT4 monobodies were stably bound to CRT. Exposure to 10 Gy IR decreased the viability of CT-26 and MC-38 tumor cells in a time-dependent manner until 72 h, and increased the expression of the ICD marker ecto-CRT (CRT exposed on the cell surface) and the immune checkpoint marker PD-L1 until 48 h. IR enhanced the cytotoxicity of CRT3LP and CRT4LP in CT-26 and MC-38 tumor cells, and increased reactive oxygen species (ROS) levels. In mice bearing CT-26 and MC-38 subcutaneous tumors treated with 6 Gy IR, Rluc8-conjugated CRT-specific monobodies (CRT3-Rluc8 and CRT4-Rluc8) specifically targeted tumor tissues, and CRT3LP and CRT4LP increased total ROS levels in tumor tissues, thereby enhancing the antitumor efficacy of RT. Tumor tissues from these mice showed increased mature dendritic, CD4+ T, and CD8+ T cells and pro-inflammatory cytokines (IFNγ and TNFα) and decreased regulatory T cells, and the expression of tumor cell proliferation markers (Ki67 and CD31) was downregulated. These data indicate that the combination of IR and CRT-targeting L-ASNases activated and reprogramed the immune system of the tumor microenvironment. Consistent with these data, an immune checkpoint inhibitor (anti-PD-L1 antibody) markedly increased the therapeutic efficacy of combined IR and CRT-targeting L-ASNases. Conclusion: CRT-specific L-ASNases are useful as additive drug candidates in tumors treated with RT, and combination treatment with anti-PD-L1 antibody increases their therapeutic efficacy.

Dataset Information

Anti-PD-1 antibody armored γδ T cells enhance anti-tumor efficacy in ovarian cancer.

Publications

Anti-PD-1 antibody armored γδ T cells enhance anti-tumor efficacy in ovarian cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets