Hashizume Akihito, Umemoto Susumu, Yokose Tomoyuki, Nakamura Yoshiyasu, Yoshihara Mitsuyo, Shoji Kahori, Wada Satoshi, Miyagi Yohei, Kishida Takeshi, Sasada Tetsuro
Department of Urology, Kanagawa Cancer Center, Yokohama, Japan.
Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan.
Oncotarget. 2018 Sep 25;9(75):34066-34078. doi: 10.18632/oncotarget.26122.
Immune checkpoint molecules, such as PD-1/PD-L1, are reported to be closely associated with suppression of antitumor immunity, and their inhibitors have been used to treat various cancers including bladder cancer. However, there have been only a few studies investigating the effects of Bacillus Calmette-Guerin (BCG) administration on expression of the immune checkpoint molecules in bladder cancer. The current study examined the expression of PD-L1 and PD-L2 before and after BCG in non-muscle-invasive bladder cancer (NMIBC) patients. Tissue microarrays of 22 BCG-resistant NMIBC patients were stained by immunohistochemistry with antibodies against PD-L1, PD-L2, and CD8, and were compared between before and after BCG. The expression levels of PD-L1, but not of PD-L2, were significantly increased after BCG treatment on tumor cells (p < 0.001) and tumor-infiltrating inflammatory cells (p = 0.030) within tumor tissues, as well as on inflammatory cells within non-tumor normal tissues (p = 0.003). Although CD8 T cells were significantly increased within tumor tissues (p = 0.005) and non-tumor normal tissues (p = 0.007) after BCG treatment, they might be not effective for anti-tumor immunity. This study demonstrated for the first time that expression of PD-L1, which might contribute to the immune escape mechanism, was enhanced on tumor tissue after BCG treatment in BCG-resistant NMIBC patients. Our finding thus propose that immunotherapy with anti-PD-1/PD-L1 antibodies could be feasible as combination treatment with BCG or as secondary treatment at relapse after BCG in NMIBC patients.
据报道，免疫检查点分子，如PD-1/PD-L1，与抗肿瘤免疫抑制密切相关，其抑制剂已被用于治疗包括膀胱癌在内的各种癌症。然而，关于卡介苗（BCG）给药对膀胱癌免疫检查点分子表达影响的研究较少。本研究检测了非肌层浸润性膀胱癌（NMIBC）患者BCG治疗前后PD-L1和PD-L2的表达。对22例卡介苗耐药的NMIBC患者的组织芯片进行免疫组织化学染色，使用抗PD-L1、PD-L2和CD8的抗体，并比较卡介苗治疗前后的情况。卡介苗治疗后，肿瘤组织内的肿瘤细胞（p < 0.001）和肿瘤浸润性炎症细胞（p = 0.030）以及非肿瘤正常组织内的炎症细胞（p = 0.003）上PD-L1的表达水平显著升高，但PD-L2的表达水平未显著升高。尽管卡介苗治疗后肿瘤组织（p = 0.005）和非肿瘤正常组织（p = 0.007）内的CD8 T细胞显著增加，但它们可能对抗肿瘤免疫无效。本研究首次证明，在卡介苗耐药的NMIBC患者中，卡介苗治疗后肿瘤组织上可能有助于免疫逃逸机制的PD-L1表达增强。因此，我们的研究结果表明，抗PD-1/PD-L1抗体免疫治疗作为与卡介苗的联合治疗或作为NMIBC患者卡介苗复发后的二线治疗可能是可行的。
