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.

The synergistic antitumor activity of 3-(2-nitrophenyl) propionic acid-paclitaxel nanoparticles (NPPA-PTX NPs) and anti-PD-L1 antibody inducing immunogenic cell death

“…The number of Tregs expressed Foxp3þ decreased in the monotherapy and combined therapy, which confirmed the reversal of immunosuppression (Zhu & Chen, 2019). Current research shows that tumors might escape immune surveillance via PD-1/PD-L1 axis upon NPPA-PTX NPs chemotherapy (Peng et al, 2015;Yang et al, 2020) which highlights the significance of combining the chemotherapeutic agent NPPA-PTX NPs with immune checkpoint blockade molecules like aPD-L1. In addition, it was known that 'hot' tumors are T cell-inflamed and highly immunogenic which are usually good responders to immune checkpoint inhibitors (Li & Burgess, 2020).…”

“…The administrated dosage is an important factor for the stimulation of antitumor immune response, especially for drugs with cytotoxicity (Sharma & Allison, 2015). It was reported that, even at a low dose (10 mg kg À1 ), nano-PTX could significantly suppress tumor growth more efficiently than immune activation alone (Yang et al, 2020). However, chemotherapy at a high dosage produced indiscriminate cytotoxicity both in tumors and immune cells (DCs, T cells) (Mathios et al, 2016).…”

“…PTX is an effective antitumor chemotherapeutic agent with wide clinical use (Meng et al, 2016). There is growing evidence indicating that PTX can induce ICD and augment antitumor immunity (Kim et al, 2020;Lau et al, 2020;Su et al, 2020;Tu et al, 2020;Yang et al, 2020;Wang et al, 2021). The phase 3 study, IMpassion130, evaluated atezolizumab, a monoclonal antibody targeting PD-L1, plus nab-paclitaxel compared with placebo plus nab-paclitaxel as a first-line treatment for patients with unresectable locally advanced or metastatic triple-negative breast cancer (Schmid et al, 2018), which was approved by the U.S. FDA in 2019.…”

Evaluation of the efficacy and safety of a new formulation‐lipid emulsion‐based PTX injection: Pharmacokinetics, tissue distributions and anticancer effect on human gastric cancer cells in vitro

“…Since PTX is highly lipophilic and poorly soluble in water, several new formulations have been investigated which can confer beneficial effects on its pharmacology and toxicology (Jiang et al, 2020;Kitayama et al, 2017;Yang et al, 2020). However, the components of an intravenous formulation may affect the clearance, protein binding and distribution of the drug.…”

Firing up the Tumor Microenvironment with Nanoparticle-Based Therapies

“…Improved tumor suppression of paclitaxel micelles was in line with a higher level of ICD. It has been proven that paclitaxel-induced ICD could promote antigen presentation by dendritic cells and activate antitumor immunity [ 33 ]. Instead of utilizing collagenase as pretreatment, Huang et al designed a novel collagenase IV and clusterin modified polycaprolactone-polyethylene glycol (PCL-PEG) nanoparticles that load doxorubicin, which exhibited impressive ECM penetration and anti-tumor effects both in vitro and in vivo [ 34 ].…”