Local Release of TGF‐β Inhibitor Modulates Tumor‐Associated Neutrophils and Enhances Pancreatic Cancer Response to Combined Irreversible Electroporation and Immunotherapy

Abstract

Pancreatic cancer is a deadly disease with little response to standard therapies. Irreversible electroporation (IRE) has emerged as a novel ablative technique for the clinical treatment of pancreatic cancer. Combinations of IRE and immunotherapies, including anti-programmed death 1 (𝜶PD1) immune checkpoint blockade, have shown promising efficacy in both preclinical and clinical studies. However, tumor recurrence remains an obstacle that needs to be overcome. It herein is shown that IRE induces a substantial infiltration of neutrophils into pancreatic tumors. These neutrophils are then polarized into a protumor phenotype by immunosuppressive cues, in particular transforming growth factor 𝜷 (TGF-𝜷). Using glutathione-responsive degradable mesoporous silica nanoparticles loaded with SB525334, an inhibitor of TGF-𝜷1 receptor, it is demonstrated that local inhibition of TGF-𝜷 within the tumor microenvironment promotes neutrophil polarization into an antitumor phenotype, enhances pancreatic cancer response to combined IRE and 𝜶PD1 therapy, and induces long-term antitumor memory. The therapeutic efficacy is also attributed to tumor infiltration by CD8 + cytotoxic T cells, depletion of regulatory T cells, and maturation of antigen-presenting dendritic cells. Thus, modulating neutrophil polarization with nanomedicine is a promising strategy for treating pancreatic cancer.

Tumor Cell‐Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis

“…Some researchers raised the N1 and N2 terms to define neutrophils with pro‐inflammatory and anti‐inflammatory features, respectively. [ 12 ] By applying marker genes of N1 and N2, we found that most of N1‐associated genes were significantly down‐regulated in Neu‐ Setd2 KO compared to Neu‐ Setd2 WT , such as Tnfa , Ifng, Nos2 , Icam1 , Cxcl9 , and Cxcl10 . Moreover, some N2‐associated genes like Mrc1 , Il10 , and Ccl7 were further upregulated in Neu‐ Setd2 KO compared to Neu‐ Setd2 WT (Figure S4F , Supporting Information).…”

Roles of tumor-associated neutrophils in tumor metastasis and its clinical applications

“…For example, mesoporous silica nanoparticles loaded with SB525334, an inhibitor of the TGF-β1 receptor, were designed in mouse models of pancreatic cancer. Local inhibition of TGF-β increases neutrophil polarization towards an anticancer phenotype in the TME and induces long-term antitumor memory ( Peng et al, 2022 ). Similarly, another study revealed that a novel CRC-derived exosomal circPACRGL facilitated TGF-β1 expression and induced differentiation of N1 to N2 in mouse models ( Shang et al, 2020 ).…”

Cancer-Associated Fibroblast-Targeted Delivery of Captopril to Overcome Penetration Obstacles for Enhanced Pancreatic Cancer Therapy

“…Transforming growth factor-beta1 (TGF-β1) is a critical cytokine in the activation of CAFs and the demoplastic transformation of pancreatic tumors. Reducing the production of TGF-β1 or blockade of its relative signaling pathways represents a potent approach to downregulate stromal obstacles and enhances the penetration of chemotherapeutic drugs. , …”

“…Reducing the production of TGF-β1 or blockade of its relative signaling pathways represents a potent approach to downregulate stromal obstacles and enhances the penetration of chemotherapeutic drugs. 28,29 Angiotensin receptor blockers (ARBs) and angiotensinconverting enzyme inhibitor (ACEI) make up a group of hypertension drugs commonly prescribed in clinical applications. 30,31 Captopril is a common ACEI, which exerts therapeutic functions via Smad (abbreviation for drosophila mothers against decapentaplegic protein) and other signaling pathways.…”