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Anti-CD40 mAb enhanced efficacy of anti-PD1 against osteosarcoma.

ABSTRACT: The overall survival rate of patients with osteosarcoma has remained stagnant at 15-30% for several decades. Although immunotherapy has revolutionized the oncology field, largely attributed to the success of immune-checkpoint blockade, the durability and efficacy of anti-PD1 (programmed cell death protein 1) mAb vary across different malignancies. Among the major reasons for tumor resistance to this immune checkpoint therapy is the absence of tumor-infiltrating cytotoxic T lymphocytes. However, the presence of intratumor exhausted PD1^hi T cells also contributes to insensitivity to anti-PD1 treatment. In this study, we established the osteosarcoma mouse tumor model resistant to anti-PD1 mAb that harbored PD1^hi T cells. Furthermore, flow cytometry analysis of tumor infiltrating leukocytes after treatment was used as a screening platform to identify agents that could re-sensitize T cells to anti-PD1 mAb. Results showed that anti-CD40 mAb treatment converted PD1^hi T cells to PD1^lo T cells, reversing phenotypic T cell exhaustion and sensitizing anti-PD1 refractory tumors to respond to anti-PD1 mAb. Results also showed that intratumor Treg presented with a less activated and attenuated suppressive phenotype after anti-CD40 mAb treatment. Our study provides proof of concept to systematically identify immune conditioning agents, which are able to convert PD1^hi T cells to PD1^lo T cells, with clinical implications in the treatment against refractory osteosarcoma to anti-PD1 mAb.

SUBMITTER: Zhang J

PROVIDER: S-EPMC6593232 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Anti-CD40 mAb enhanced efficacy of anti-PD1 against osteosarcoma.

Zhang Jingzhe J Li Ye Y Yang Shoujun S Zhang Lening L Wang Wenjun W

Journal of bone oncology 20190612

The overall survival rate of patients with osteosarcoma has remained stagnant at 15-30% for several decades. Although immunotherapy has revolutionized the oncology field, largely attributed to the success of immune-checkpoint blockade, the durability and efficacy of anti-PD1 (programmed cell death protein 1) mAb vary across different malignancies. Among the major reasons for tumor resistance to this immune checkpoint therapy is the absence of tumor-infiltrating cytotoxic T lymphocytes. However, ...[more]

PMID: 31293882

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Project description:ObjectiveTitanium dioxide nanoparticles (TiO2) nanoparticles have been widely explored in the prevention of cancer risk. Due to the difficult solubility of TiO2 nanoparticles, it is essential to synthesize new surfactants to increase its bioavailability and anti-tumor activity and reduce its cytotoxicity. Furthermore, oxidative and inflammation are closely associated with the osteosarcoma risk. Chitosan has biocompatibility, antioxidant and anti-inflammatory properties. The effects of chitosan-coated TiO2-embedded paclitaxel nanoparticles on an osteosarcoma model were explored.MethodsAn osteosarcoma model was established and chitosan-coated TiO2-embedded paclitaxel nanoparticles were prepared using a freeze-drying strategy. The morphological characteristics of nanoparticles were observed using scanning electron microscopy (SEM). The physicochemical properties of nanoparticle were evaluated by X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy. The cytotoxicity was tested by using human osteoblast cells hFob1.19 and osteosarcoma cells 143B. Osteosarcoma mice were treated with PBS buffer, paclitaxel, TiO2-embedded paclitaxel and chitosan-coated TiO2-embedded paclitaxel nanoparticles. The biomarkers of oxidative-inflammatory status, anti-tumor activities and survival rates of the model were measured.ResultsXRD analysis showed that the peaks of chitosan/TiO2 (anatase) were consistent with those of crystalline TiO2 and broad phase of chitosan. The FTIR spectrum indicated the relevant functional groups in TiO2. Chitosan-coated TiO2-embedded paclitaxel nanoparticles had good biocompatibility and improve antioxidant and anti-inflammatory properties in the osteosarcoma model. Chitosan-coated TiO2-embedded paclitaxel nanoparticles was less toxic to the cells hFob1.19 and more toxic to the cells 143B than TiO2-embedded paclitaxel nanoparticles. Chitosan-coated TiO2-embedded paclitaxel nanoparticles showed significant antitumor activity and increased the survival rate of the osteosarcoma model (P < 0.05).ConclusionsChitosan improved anti-tumor potential of TiO2-embedded paclitaxel nanoparticles in the prevention of osteosarcoma.

Dataset Information

Anti-CD40 mAb enhanced efficacy of anti-PD1 against osteosarcoma.

Publications

Anti-CD40 mAb enhanced efficacy of anti-PD1 against osteosarcoma.

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