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Delivery of an ectonucleotidase inhibitor with ROS-responsive nanoparticles overcomes adenosine-mediated cancer
Chengqiong Mao1, Stacy Yeh2, Juan Fu1
1Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Abstract:
Tumor evasion of immune destruction is associated with the production of immunosuppressive adenosine in the tumor microenvironment (TME). Anticancer therapies can trigger adenosine triphosphate (ATP) release from tumor cells, causing rapid formation of adenosine by the ectonucleotidases CD39 and CD73, thereafter exacerbating immunosuppression in the TME. The goal of this study was to develop an approach to facilitate cancer therapy-induced immunogenic cell death including ATP release and to limit ATP degradation into adenosine, in order to achieve durable antitumor immune response. Our approach was to construct reactive oxygen species (ROS)-producing nanoparticles that carry an ectonucleotidase inhibitor ARL67156 by electronic interaction and phenylboronic ester. Upon near-infrared irradiation, nanoparticle-produced ROS induced ATP release from MOC1 cancer cells in vitro and triggered the cleavage of phenylboronic ester, facilitating the release of ARL67156 from the nanoparticles. ARL67156 prevented conversion of ATP to adenosine and enhanced anticancer immunity in an MOC1-based coculture model. We tested this approach in mouse tumor models. Nanoparticle-based ROS-responsive drug delivery reprogramed the immunogenic landscape in tumors, eliciting tumor-specific T cell responses and tumor regression, conferring long-term survival in mouse models. We demonstrated that TME reprograming sets the stage for response to anti-programmed cell death protein 1 (PD1) immunotherapy, and the combination resulted in tumor regression in a 4T1 breast cancer mouse model that was resistant to PD1 blockade. Furthermore, our approach also induced immunological effects in patient-derived organotypic tumor spheroid model, suggesting potential translation of our nanoparticle approach for treating human cancers.
Insights
New nanoparticles release ATP and inhibit adenosine, boosting anti-cancer immunity. This approach enhances tumor cell death and T cell responses, leading to tumor regression and long-term survival in mouse models.
Area of Science:
- Biomedical Engineering
- Cancer Immunology
- Nanomedicine
Background:
- Tumor cells evade immune destruction via immunosuppressive adenosine in the tumor microenvironment (TME).
- Anticancer therapies can increase adenosine levels by promoting adenosine triphosphate (ATP) release and subsequent degradation by CD39 and CD73.
- Elevated adenosine exacerbates immunosuppression, hindering effective antitumor immune responses.
Purpose of the Study:
- To develop a nanoparticle-based strategy to enhance cancer therapy-induced immunogenic cell death.
- To limit adenosine production in the TME by inhibiting ectonucleotidases.
- To achieve durable antitumor immune responses and tumor regression.
Main Methods:
- Constructed reactive oxygen species (ROS)-producing nanoparticles encapsulating the ectonucleotidase inhibitor ARL67156.
- Utilized near-infrared irradiation to trigger ROS production, inducing ATP release and ARL67156 release from nanoparticles.
- Evaluated the approach in vitro (MOC1 cancer cells) and in vivo (mouse tumor models), including combination with anti-PD1 immunotherapy.
Main Results:
- Nanoparticles induced ATP release and inhibited ATP-to-adenosine conversion via ARL67156, enhancing anti-cancer immunity in vitro.
- In vivo studies showed nanoparticle-mediated ROS production reprogramed the tumor immune landscape, eliciting tumor-specific T cell responses and tumor regression.
- Combination therapy demonstrated efficacy in a PD1-resistant breast cancer model and showed promise in patient-derived organotypic tumor spheroids.
Conclusions:
- The developed ROS-responsive nanoparticles effectively enhance anti-cancer immunity by modulating the TME.
- This approach facilitates immunogenic cell death, promotes T cell responses, and overcomes resistance to PD1 blockade.
- The nanoparticle strategy holds potential for translation into effective human cancer therapies.
