A tumor cell membrane-coated self-amplified nanosystem as a nanovaccine to boost the therapeutic effect of anti-PD-L1 antibody

Abstract

To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosuppressive cancers like triple-negative breast cancer (TNBC), induction of immunogenic cell death (ICD) at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint inhibitors. Herein, a self-amplified biomimetic nanosystem, mEHGZ, was constructed by encapsulation of epirubicin (EPI), glucose oxidase (Gox) and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin (CRT) over-expressed tumor cell membrane. EPI acts as an ICD inducer, Gox and hemin medicate the cascade generation of reactive oxygen species (ROS) to strengthen the ICD effect, and CRT-rich membrane as “eat me” signal promote presentation of the released antigens by dendritic cells (DCs) to invoke the tumor-immunity cycle. The biomimetic delivery system displays an amplified ICD effect via Gox oxidation, hydroxyl radical generation and glutathione (GSH) depletion. The induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes (CTLs) infiltration, reversing an immunosuppressive tumor microenvironment to an immunoresponsive one. Treatment with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis, supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 antibody. This self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.

Graphical abstract

A biomimetic nanosystem encapsulates epirubicin (EPI), glucose oxidase (Gox) and hemin in the core of ZIF-8 nanoparticles and coats with calreticulin (CRT) over-expressed tumor cell membranes as the outermost layer (mEHGZ), which induces cascade-amplified ICD effect to promote dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) infiltration into tumor site. These create an immunoactivated tumor microenvironment to boost anti-PD-L1 antibody therapeutic effect.

Highlights

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  To improve the response rate of immune checkpoint inhibitor in triple-negative breast cancer, a self-amplified biomimetic nanosystem was prepared.

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  The nanosystem displayed an amplified immunogenic cell death (ICD) effect via hydroxyl radical generation and glutathione depletion.

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  The potent ICD effect has promoted dendritic cells maturation and cytotoxic T lymphocytes infiltration into tumor sites to boost the anti-PD-L1 antibody therapeutic effectto boost the anti-PD-L1 antibody therapeutic effect.

Abstract

Abstract.