Department of Surgery, University of Rochester Medical Center, Rochester, New York.
Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York.
Clin Cancer Res. 2022 Jan 1;28(1):150-162. doi: 10.1158/1078-0432.CCR-21-2495. Epub 2021 Dec 3.
PURPOSE: Stereotactic body radiotherapy (SBRT) is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC), which can effectively prime cytotoxic T cells by inducing immunogenic tumor cell death in preclinical models. SBRT effects on human PDAC have yet to be thoroughly investigated; therefore, this study aimed to characterize immunomodulation in the human PDAC tumor microenvironment following therapy. EXPERIMENTAL DESIGN: Tumor samples were obtained from patients with resectable PDAC. Radiotherapy was delivered a median of 7 days prior to surgical resection, and sections were analyzed by multiplex IHC (mIHC), RNA sequencing, and T-cell receptor sequencing (TCR-seq). RESULTS: Analysis of SBRT-treated tumor tissue indicated reduced tumor cell density and increased immunogenic cell death relative to untreated controls. Radiotherapy promoted collagen deposition; however, vasculature was unaffected and spatial analyses lacked evidence of T-cell sequestration. Conversely, SBRT resulted in fewer tertiary lymphoid structures and failed to lessen or reprogram abundant immune suppressor populations. Higher percentages of PD-1 T cells were observed following SBRT, and a subset of tumors displayed more clonal T-cell repertoires. CONCLUSIONS: These findings suggest that SBRT augmentation of antitumor immunogenicity may be dampened by an overabundance of refractory immunosuppressive populations, and support the continued development of SBRT/immunotherapy combination for human PDAC.
目的:立体定向体部放疗(SBRT)是一种新兴的治疗胰腺导管腺癌(PDAC)的方法,它可以通过在临床前模型中诱导免疫原性肿瘤细胞死亡来有效地激活细胞毒性 T 细胞。SBRT 对人类 PDAC 的影响尚未得到彻底研究;因此,本研究旨在描述治疗后人类 PDAC 肿瘤微环境中的免疫调节作用。
实验设计:从可切除的 PDAC 患者中获得肿瘤样本。放射治疗在手术切除前中位数为 7 天进行,并通过多重免疫组化(mIHC)、RNA 测序和 T 细胞受体测序(TCR-seq)进行分析。
结果:对 SBRT 治疗的肿瘤组织进行分析表明,与未治疗对照相比,肿瘤细胞密度降低,免疫原性细胞死亡增加。放射治疗促进了胶原蛋白的沉积;然而,血管不受影响,空间分析也没有证据表明 T 细胞被隔离。相反,SBRT 导致更少的三级淋巴结构,并且不能减轻或重新编程丰富的免疫抑制群体。SBRT 后观察到更多的 PD-1 T 细胞,并且一部分肿瘤显示出更多的克隆 T 细胞库。
结论:这些发现表明,SBRT 增强抗肿瘤免疫原性的作用可能被过多的难治性免疫抑制群体所抑制,并支持继续开发 SBRT/免疫疗法联合治疗人类 PDAC。
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