PD-1 Cellular Nanovesicles Carrying Gemcitabine to Inhibit the Proliferation of Triple Negative Breast Cancer Cell

Abstract

PD-1 inhibitor Keytruda combined with chemotherapy for Triple-negative breast cancer (TNBC) has been approved for FDA, successfully representing the combination therapy of immunotherapy and chemotherapy for the first time in 2020. However, PD-L1 inhibitor Tecentriq combined with albumin paclitaxel using the similar strategy failed to achieve the expected effect. Therefore, it is still necessary to explore new effective immunotherapy and chemotherapy-based combined strategies. We developed a cell membrane-derived programmed death-ligand 1(PD-1) nanovesicle to encapsulate low-dose gemcitabine (PD-1&GEM NVs) to study the effect on breast cancer in vitro and in vivo. We found that engineered PD-1&GEM NVs could synergistically inhibit the proliferation of triple-negative breast cancer, which interacted with PD-L1 in triple-negative breast cancer to disrupt the PD-L1/PD-1 immune inhibitory axis and promoted cancer cell apoptosis. Moreover, PD-1&GEM NVs had better tumor targeting ability for PD-L1 highly-expressed TNBC cells, contributing to increasing the drug effectiveness and reducing toxicity. Importantly, gemcitabine-encapsulated PD-1 NVs exerted stronger effects on promoting apoptosis of tumor cells, increasing infiltrated CD8+ T cell activation, delaying the tumor growth and prolonging the survival of tumor-bearing mice than PD-1 NVs or gemcitabine alone. Thus, our study highlighted the power of combined low-dose gemcitabine and PD-1 in the nanovesicles as treatment to treat triple-negative breast cancer.

Engineering Cell-Derived Nanovesicles for Targeted Immunomodulation

“…PD1 display is an attractive engineering strategy for targeted nanotherapeutics. The PD1/PD-L1 immune checkpoint pathway is a ubiquitous therapeutic target across many different cancer types [31]. PD-L1 is overexpressed on many tumor cells, and binding to its receptor PD1 on immune cells leads to T-cell and NK cell inactivation leading to immune evasion [32].…”

“…Thus, CDNV displaying PD1 has a multi-pronged immunomodulatory effect. Although EVs can be engineered to express PD1-targeting ligands or antibodies on their surface, their cumbersome isolation and limited yield have hindered their further development as therapeutics [31]. CDNVs generated by extrusion methods offer several advantages over naturally derived EVs that position them as promising therapeutic nanoplatforms.…”

Exosomes and mimics as novel delivery platform for cancer therapy

“…The PD-1 nanovesicles induced an antitumor immune response ( Zhang X. et al, 2018b ). Zha et al prepared gemcitabine-loaded PD-1 nanovesicles, which significantly suppressed tumor growth in mice, showing the unique advantage of PD-1-decorated exosome-mimics in cancer therapy ( Zha et al, 2022 ). Signal regulatory protein-α (SIRPα) could bind to CD47 molecules on tumors and normal tissues and release a “do not eat me” signal to prevent the phagocytosis of cells ( Ring et al, 2017 ).…”

Effect of N6-methyladenosine (m6A) regulator-related immunogenes on the prognosis and immune microenvironment of breast cancer

“…The tumor immune microenvironment (TIME) consists of protumor and antitumor immune cells, which can be reprogrammed by tumor-derived factors involved in immune escape and tumor progression (8,9). Accumulating evidence has shown that the TIME plays a critical role in the development of tumors and affects the clinical results of immune checkpoint blockade (ICB) therapies, e.g., those for blocking PD-1/L1 or CTLA-4 (10)(11)(12)(13)(14). In recent years, some studies have found a special relationship between the TIME infiltration of immune cells and N6-methyladenosine (m6A) modification (15,16).…”