Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas.
Department of Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas.
Cancer Immunol Res. 2023 Jan 3;11(1):4-12. doi: 10.1158/2326-6066.CIR-22-0379.
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. In addition, 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 programmed death-ligand 1 (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.
胰腺导管腺癌（PDAC）尽管在过去二十年中努力改善临床结果，但 5 年总生存率仍仅为 11%。治疗抵抗是这种疾病的一个标志，这是由于其密集和抑制性的肿瘤微环境（TME）。内镜超声引导下射频消融术（EUS-RFA）是一种有前途的局部消融和潜在的免疫调节疗法，适用于 PDAC。在这项研究中，我们在临床前携带 KrasG12D；Trp53R172H/+；Pdx1：Cre（KPC）的荷瘤同基因模型中进行了 RFA，分析了 RFA 后的局部和远隔影响，并将我们的发现与切除的 PDAC 标本进行了比较。我们发现 RFA 减少了体内 PDAC 肿瘤的进展，并促进了强烈的 TME 重塑。此外，我们发现肿瘤浸润中性粒细胞决定了远隔效应。通过成像质谱细胞术，我们显示 RFA 增加了 RFA 治疗肿瘤中的树突状细胞数量，并促进了显著的 CD4+和 CD8+T 细胞远隔反应。此外，RFA 增加了程序性死亡配体 1（PD-L1）的水平，并且针对 PD-L1 的检查点阻断抑制在 RFA 的情况下持续减少肿瘤生长。这项研究表明，已经显示出增加肿瘤抗原脱落的 RFA 治疗促进了抗肿瘤免疫。这在 PDAC 中至关重要，因为最近的临床免疫治疗试验并未导致总体生存率的实质性变化。
