Overcoming Resistance to Immune Checkpoint Inhibitor Therapy Using Calreticulin-Inducing Nanoparticle

Nanoparticles (NPs) have the ability to transform poorly immunogenic tumors into activated 'hot' targets. In this study, we investigated the potential of a liposome-based nanoparticle (CRT-NP) expressing calreticulin as an in-situ vaccine to restore sensitivity to anti-CTLA4 immune checkpo...

Full description

Saved in:
Bibliographic Details
Published in:Pharmaceutics 2023-06, Vol.15 (6), p.1693
Main Authors: Chandrasekar, Sri Vidhya, Singh, Akansha, Ranjan, Ashish
Format: Article
Language:English
Subjects:
Antigens
Apoptosis
calreticulin
Cell death
Cloning
Colon cancer
colon carcinoma
Colorectal cancer
Comparative analysis
Cytotoxicity
Dendritic cells
Gastrointestinal diseases
Gene expression
immune checkpoint inhibitor
Immune response
immunogenic cell death
immunoresistance
Immunotherapy
Lymphocytes
nanoparticle
Nanoparticles
Reagents
T cells
Tumors
Vaccines
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Nanoparticles (NPs) have the ability to transform poorly immunogenic tumors into activated 'hot' targets. In this study, we investigated the potential of a liposome-based nanoparticle (CRT-NP) expressing calreticulin as an in-situ vaccine to restore sensitivity to anti-CTLA4 immune checkpoint inhibitor (ICI) in CT26 colon tumors. We found that a CRT-NP with a hydrodynamic diameter of approximately 300 nm and a zeta potential of approximately +20 mV induced immunogenic cell death (ICD) in CT-26 cells in a dose-dependent manner. In the mouse model of CT26 xenograft tumors, both CRT-NP and ICI monotherapy caused moderate reductions in tumor growth compared to the untreated control group. However, the combination therapy of CRT-NP and anti-CTLA4 ICI resulted in remarkable suppression of tumor growth rates (>70%) compared to untreated mice. This combination therapy also reshaped the tumor microenvironment (TME), achieving the increased infiltration of antigen-presenting cells (APCs) such as dendritic cells and M1 macrophages, as well as an abundance of T cells expressing granzyme B and a reduction in the population of CD4+ Foxp3 regulatory cells. Our findings indicate that CRT-NPs can effectively reverse immune resistance to anti-CTLA4 ICI therapy in mice, thereby improving the immunotherapeutic outcome in the mouse model.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics15061693