Breakthrough Nanoparticle Therapy Boosts Immune Response Against Aggressive Pancreatic Cancer

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMSep 9 2024

The fibrotic tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) increases the failure rate of immune- and chemotherapy by contributing to low immune infiltration and poor vascularization of the tissue.

In a recent study published in Science Translational Medicine, a team of scientists from the University of Massachusetts showed that the delivery of lipid nanoparticles containing innate immune agonists could induce a senescence-associated secretory phenotype (SASP) consisting of inflammatory and angiogenic factors that can remodel the immune suppressive tumor microenvironment in PDAC.

​​​​​​​Study: Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer. Image Credit: mi_viri/Shutterstock.com

Background

Pancreatic ductal adenocarcinoma (PDAC) is the third major contributor to cancer-related mortality in the United States and has only a 13% five-year survival rate.

The tumor microenvironment in PDAC has desmoplastic, fibrotic stroma, and poor vascularization that increases chemoresistance, prevents effective drug delivery, and hinders the infiltration and activation of cytotoxic immune cells.

Therapies such as immune checkpoint blockers that target cytotoxic T-lymphocyte-associated proteins and programmed cell death proteins have been effective for various types of cancers but have been ineffective for PDAC.

The tumor microenvironment in PDAC is devoid of the natural killer cells, cytotoxic T cells, and dendritic cells that are required for antigen presentation and sustaining antitumor immunity, which results in resistance to immune checkpoint blockers.

Furthermore, PDAC is also characterized by driver mutations in the Kirsten rat sarcoma virus (KRAS) oncogene that suppress signaling involving interferons, lowering the antigenicity and immunogenicity of pancreatic cancer cells.

The multiple factors that contribute to the lower treatment efficacy highlight the need for a multifaceted approach to target the immune suppressive tumor microenvironment in PDAC.

About the Study

The present study used murine PDAC models and focused on the delivery of immune-stimulating therapies using lipid nanoparticles to enhance immune responses. The researchers examined whether the delivery of innate immune agonists using the lipid nanoparticles could induce SASP in the immune-suppressive PDAC tumor microenvironment.

The lipid-based nanoparticles were designed to be 40 nanometers in diameter. They were loaded with two immune-stimulatory agents — cyclic di-guanosine monophosphate (cdGMP), which is a synthetic agonist of the stimulator of interferon genes (STING), and monophosphoryl lipid A (MPLA), which is a Toll-like receptor 4 (TLR4) agonist. Furthermore, the lipid nanoparticles were coated with poly(ethylene) glycol to enhance their circulation time.

The STING pathway is involved in the regulation of type I interferon production and is a vital innate immune pathway for enhancing antitumor T cell and natural killer cell immunity.

Additionally, TLR4 is involved in activating innate immune responses and contributes to anti-tumor immunity.

Two murine PDAC models were used for the study — one in which PDAC cell lines were transplanted into the mice and another where the mice were genetically engineered to develop PDAC spontaneously.

Fluorescence labels were used to track the intravenously administered lipid nanoparticles carrying the innate immune agonists.

The distribution of the nanoparticles inside the tumor microenvironment was assessed 48 hours after the injection to determine the uptake of the nanoparticles in different tumor cells.

Furthermore, the systemic effects of the nanoparticle injection were examined by analyzing their biodistribution in other organs, such as the liver, lungs, spleen, and pancreas of mice without cancer.

Liver function tests and histopathological analyses were conducted to assess the safety profile of the lipid nanoparticles.

Additionally, combination therapies involving trametinib, a mitogen-activated protein kinase kinase (MEK) inhibitor, and the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib along with the immune-nanoparticles were also investigated for enhanced uptake and biodistribution of nanoparticles, and improved innate immune activation in PDAC models.

The gene expression of chemokines, cytokines, and type 1 interferons and the activation of innate and adaptive immune responses based on the populations of macrophages, dendritic cells, natural killer cells, and cytotoxic T cells were evaluated.

Furthermore, two weeks after the treatment, the researchers conducted histopathological assessments of the tumors to determine the long-term impact of the treatment.

Major Findings

The study found that the use of lipid nanoparticles to deliver innate immune agonists in mouse models of PDAC resulted in a significant increase in the levels of innate immunity activation and substantially enhanced tumor regression.

Various cell types in the tumor microenvironment showed increased uptake of the lipid nanoparticles carrying immune stimulants.

The innate immune agonists cdGMP and MPLA triggered the activation of numerous pro-inflammatory pathways, including type 1 interferon pathways, which improved antigen presentation and elicited both adaptive and innate immune responses.

Furthermore, this approach also led to the activation of natural killer cells and cytotoxic T cells, resulting in the regression of pancreatic tumors in the PDAC mouse models.

The combination therapy was found to overcome several immune-suppressive mechanisms in the tumor microenvironment of PDAC, including low antigen presentation and low levels of immune cell infiltration.

The type 1 interferon signaling through TLR4 and STING pathways was found to be crucial for overcoming the immune-suppressive effects.

Conclusions

Overall, the findings indicated that reactivating antigen presentation and inflammatory pathways was key to surmounting the immune evasive characteristics of PDAC.

The use of lipid nanoparticles to deliver innate immune agonists to the tumor microenvironment resulted in enhanced antigen presentation and activation of adaptive and innate immune responses.

The study highlights the potential for the successful use of a combination therapy involving immune agonists and systemic tumor-targeting drugs to activate durable anti-cancer immunity in PDAC.