Yamamoto Junya, Takahashi Yutaka, Minami Kazumasa, Tamari Keisuke, Katsuki Shohei, Takenaka Wataru, Tatekawa Shotaro, Hayashi Kazuhiko, Seo Yuji, Isohashi Fumiaki, Ogawa Kazuhiko, Koizumi Masahiko
Department of Medical Physics and Engineering, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Department of Radiation Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Cancers (Basel). 2022 Apr 22;14(9):2087. doi: 10.3390/cancers14092087.
Pancreatic cancer is an extremely treatment-resistant neoplasm to chemotherapy and immunotherapy. The combination of photon beam irradiation and anti-CTLA-4 antibody (C4) for the anti-tumor effect enhancement at local and distant tumors (abscopal tumors) was investigated using the pancreatic ductal adenocarcinoma (PDAC) mouse model. Pan02 cells were bilaterally inoculated to both legs of C57BL/6 mice. High dose photon beams in a hypofractionation or a single fraction were delivered to the tumors on one leg. Monotherapy with C4 via i.p. was not effective for PDAC. The high dose irradiation to the local tumors produced significant shrinkage of irradiated tumors but did not induce the abscopal responses. In contrast, the combination therapy of high dose photon beam irradiation in both hypofractionation and a single fraction with C4 enhanced the anti-tumor effect for abscopal tumors with significantly prolonged overall survival. The flow cytometric analysis revealed that the combination therapy dramatically decreased the regulatory T cell (Treg) proportion while increasing the cytotoxic T lymphocytes in both local and abscopal tumors. These results suggest that high dose photon beam irradiation plays an important role in C4 therapy to enhance the abscopal response with immune microenvironment changes in PDAC, regardless of the fractionation in radiation therapy.
胰腺癌是一种对化疗和免疫疗法极具耐药性的肿瘤。利用胰腺导管腺癌（PDAC）小鼠模型，研究了光子束照射与抗CTLA-4抗体（C4）联合使用对局部和远处肿瘤（远隔效应肿瘤）抗肿瘤作用的增强效果。将Pan02细胞双侧接种到C57BL/6小鼠的两条腿上。对一条腿上的肿瘤给予大分割或单次分割的高剂量光子束照射。通过腹腔注射C4进行单一疗法对PDAC无效。对局部肿瘤进行高剂量照射可使照射的肿瘤显著缩小，但未诱导出远隔效应反应。相比之下，大分割和单次分割的高剂量光子束照射与C4联合治疗增强了对远隔效应肿瘤的抗肿瘤作用，并显著延长了总生存期。流式细胞术分析显示，联合治疗显著降低了调节性T细胞（Treg）比例，同时增加了局部和远隔效应肿瘤中的细胞毒性T淋巴细胞。这些结果表明，无论放射治疗的分割方式如何，高剂量光子束照射在C4治疗中都起着重要作用，可通过改变PDAC的免疫微环境来增强远隔效应反应。
