Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) presents a 5-year overall survival rate of 11%, despite efforts to improve clinical outcomes in the past two decades. Therapeutic resistance is a hallmark of this disease, due to its dense and suppressive tumor microenvironment (TME). Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) is a promising local ablative and potential immunomodulatory therapy for PDAC. In this study, we performed RFA in a preclinical tumor-bearing KrasG12D; Trp53R172H/+; Pdx1:Cre (KPC) syngeneic model, analyzed local and abscopal affects after RFA and compared our findings with resected PDAC specimens. We found that RFA reduced PDAC tumor progression in vivo and promoted strong TME remodeling. Additionally, we discovered tumor-infiltrating neutrophils determined abscopal effects. Using imaging mass cytometry, we showed that RFA elevated dendritic cell numbers in RFA-treated tumors and promoted a significant CD4+ and CD8+ T-cell abscopal response. In addition, RFA elevated levels of PD-L1 and checkpoint blockade inhibition targeting PD-L1 sustained tumor growth reduction in the context of RFA. This study indicates RFA treatment, which has been shown to increase tumor antigen shedding, promotes antitumor immunity. This is critical in PDAC where recent clinical immunotherapy trials have not resulted in substantial changes in overall survival.

A Booster for Radiofrequency Ablation: Advanced Adjuvant Therapy via In Situ Nanovaccine Synergized with Anti-programmed Death Ligand 1 Immunotherapy for Systemically Constraining Hepatocellular Carcinoma

“…Furthermore, the expression of tumor-promoting molecules, CD163 and Mcam was reduced, and productions of cytokines and chemokines, such as Cxcl9, CD8a, Gzmb, and Gzmf, were increased post RFA+LDHs treatment (Figure C). Similar to previous studies, ,, the expression of PD-L1 was up-regulated after incomplete RFA, which was observed in the RFA+LDHs group as well (Figure S1F). These results indicate that LDHs boosted the immune response induced by RFA, especially concerning DCs and antigen processing/presentation.…”

“…In general, the response efficiency of αPD-L1 Ab is strongly related to the expression of PD-L1 on cancerous cell surfaces and the infiltration of immune cells inside tumor tissues. Both previous studies ,, and current study have proved that RFA itself increased the expression of PD-L1 (Figure S1F) in malignant tissues. Furthermore, assays above systemically demonstrated LDHs-cGAMP could act as a powerful nanovaccine with significant promotions on the tumor infiltration of immune cells and the killing functions of cytotoxic lymphocytes (Figures and ).…”

“…Such thermal therapy could induce a certain immune response via cell debris released from denatured malignant tissues . However, the immunoreaction is mild, while a series of immunosuppressive effects would also be triggered, for instance, amplified expression of PD1 , /PD-L1 , in the residual tumor and suppression of CD8 + T cells caused by the aggregation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) . More importantly, it is also challenging for RFA to deal with irregular lesions or typical HCC symptoms, including intrahepatic metastasis, multicenter recurrence, and small satellite nodules .…”

Microwave ablation enhances the systemic immune response in patients with lung cancer

“…Hyperthermia generated by thermal ablation releases TAAs, which are absorbed by antigen-presenting cells for presentation to T cells to stimulate specific antitumor immune responses ( 67 ). Faraoni et al ( 68 ) reported that RFA notably increases the number of dendritic cells in pancreatic ductal adenocarcinoma and induces CD4 + and CD8 + T cell-mediated abscopal effects. Kanegasaki and Tsuchiya ( 69 ) reported that RFA modulates an antitumor immune response in a CC-chemokine receptor 1-dependent manner.…”

Neutrophils in the era of single-cell RNA sequencing: functions and targeted therapies in cancer

“…An anti-FcγRIIIB-antigen conjugate is a promising therapeutic approach because neutrophils can be induced to adopt properties of dendritic cells and promote the anti-tumor immunity of CD8+ T cells 33 . Finally, another study showed that radiation therapy can also polarize immunosuppressive TANs into an anti-tumor phenotype 34 .…”