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Nanomicelle protects the immune activation effects of Paclitaxel and sensitizes tumors to anti-PD-1 Immunotherapy.

ABSTRACT: Paclitaxel (PTX) has shown pleiotropic immunologic effects on the tumor microenvironment, and nanomicelle has emerged as a promising strategy for PTX delivery. However, the detailed mechanisms remain to be fully elucidated. Meanwhile, immunogenic cell death (ICD) is an effective approach to activate the immune system. This study investigated the ICD effect of PTX and how nanomicelle affected the immune-activation ability of PTX. Methods: The ICD effects of PTX were identified via the expression of ICD markers and cell vaccine experiment. Tumor size and overall survival in multiple animal models with treatment were monitored to evaluate the antitumor effects. The mechanisms of PTX-induced ICD and antitumor immunity were determined by detecting gene expression related to ER stress and analyzing immune cell profile in tumor after treatment. Results: We revealed the immune-regulation mechanism of PTX nanomicelle by inducing ICD, which can promote antigen presentation by dendritic cells (DCs) and activate antitumor immunity. Notably, nanomicelle encapsulation protected the ICD effects and immune activation, which were hampered by immune system impairment caused by chemotherapy. Compared with traditional formulations, a low dose of nanomicelle-encapsulated PTX (nano-PTX) treatment induced immune-dependent tumor control, which increased the infiltration and function of both T cells and DCs within tumors. However, this antitumor immunity was hampered by highly expressed PD-1 on tumor-infiltrating CD8+ T cells and upregulated PD-L1 on both immune cells and tumor cells after nano-PTX treatment. Combination therapy with a low dose of nano-PTX and PD-1 antibodies elicited CD8+ T cell-dependent antitumor immunity and remarkably improved the therapeutic efficacy. Conclusions: Our results provide systemic insights into the immune-regulation ability of PTX to induce ICD, which acts as an inducer of endogenous vaccines through ICD effects, and also provides an experimental basis for clinical combination therapy with nano-PTX and PD-1 antibodies.

SUBMITTER: Yang Q

PROVIDER: S-EPMC7381738 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Nanomicelle protects the immune activation effects of Paclitaxel and sensitizes tumors to anti-PD-1 Immunotherapy.

Yang Qianmei Q Shi Gang G Chen Xiaolei X Lin Yi Y Cheng Lin L Jiang Qingyuan Q Yan Xi X Jiang Ming M Li Yiming Y Zhang Hantao H Wang Huiling H Wang Yuan Y Wang Qingnan Q Zhang Yujing Y Liu Yi Y Su Xiaolan X Dai Lei L Tang Minghai M Li Jia J Zhang Lan L Qian Zhiyong Z Yu Dechao D Deng Hongxin H

Theranostics 20200709 18

Paclitaxel (PTX) has shown pleiotropic immunologic effects on the tumor microenvironment, and nanomicelle has emerged as a promising strategy for PTX delivery. However, the detailed mechanisms remain to be fully elucidated. Meanwhile, immunogenic cell death (ICD) is an effective approach to activate the immune system. This study investigated the ICD effect of PTX and how nanomicelle affected the immune-activation ability of PTX. <b>Methods:</b> The ICD effects of PTX were identified via the expr ...[more]

PMID: 32724476

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Project description:BackgroundAlthough anti-programmed cell death protein 1 (PD-1) immunotherapy is greatly effective in melanoma treatment, low response rate and treatment resistance significantly hinder its efficacy. Tumor cell ferroptosis triggered by interferon (IFN)-γ that is derived from tumor-infiltrating CD8+ T cells greatly contributes to the effect of immunotherapy. However, the molecular mechanism underlying IFN-γ-mediated ferroptosis and related potentially promising therapeutic strategy warrant further clarification. MicroRNAs (miRNAs) participate in ferroptosis execution and can be delivered systemically by multiple carriers, which have manifested obvious therapeutic effects on cancer.MethodsMiRNAs expression profile in IFN-γ-driven ferroptosis was obtained by RNA sequencing. Biochemical assays were used to clarify the role of miR-21-3p in IFN-γ-driven ferroptosis and the underlying mechanism. MiR-21-3p-loaded gold nanoparticles were constructed and systemically applied to analyze the role of miR-21-3p in anti-PD-1 immunotherapy in preclinical transplanted tumor model.ResultsMiRNAs expression profile of melanoma cells in IFN-γ-driven ferroptosis was first obtained. Then, upregulated miR-21-3p was proved to facilitate IFN-γ-mediated ferroptosis by potentiating lipid peroxidation. miR-21-3p increased the ferroptosis sensitivity by directly targeting thioredoxin reductase 1 (TXNRD1) to enhance lipid reactive oxygen species (ROS) generation. Furthermore, miR-21-3p overexpression in tumor synergized with anti-PD-1 antibody by promoting tumor cell ferroptosis. More importantly, miR-21-3p-loaded gold nanoparticles were constructed, and the systemic delivery of them increased the efficacy of anti-PD-1 antibody without prominent side effects in preclinical mice model. Ultimately, ATF3 was found to promote miR-21-3p transcription in IFN-γ-driven ferroptosis.ConclusionsMiR-21-3 p upregulation contributes to IFN-γ-driven ferroptosis and synergizes with anti-PD-1 antibody. Nanoparticle delivery of miR-21-3 p is a promising therapeutic approach to increase immunotherapy efficacy without obvious systemic side effects.

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Nanomicelle protects the immune activation effects of Paclitaxel and sensitizes tumors to anti-PD-1 Immunotherapy.

Publications

Nanomicelle protects the immune activation effects of Paclitaxel and sensitizes tumors to anti-PD-1 Immunotherapy.

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