Kubo Terufumi, Hirohashi Yoshihiko, Matsuo Kazuhiko, Sonoda Tomoko, Sakamoto Hiroki, Furumura Kiyoshi, Tsukahara Tomohide, Kanaseki Takayuki, Nakatsugawa Munehide, Hirano Hiroshi, Furuhata Tomohisa, Takemasa Ichiro, Hasegawa Tadashi, Torigoe Toshihiko
Department of Pathology, Sapporo Medical University, School of Medicine, Sapporo, Japan
Sapporo Clinical Laboratory Inc., Sapporo, Japan.
Anticancer Res. 2017 Mar;37(3):1289-1295. doi: 10.21873/anticanres.11446.
Accumulating evidence indicates that immune checkpoint inhibition-mediated cancer immunotherapies greatly improve the prognosis of certain types of cancer. This approach is now becoming a standard therapy, joining surgery, radiotherapy, and chemotherapy. Because the costs of antibody drugs are now a socioeconomic burden in many countries, an urgent need in cancer immunotherapy is the identification of relevant biomarkers that can predict therapy efficacy. Recent studies have reported that colorectal adenocarcinoma with hereditary or sporadic deficiency in mismatch repair (MMR) proteins has high antigenicity and that detection of these proteins could be a promising way to estimate clinical response. In this study of 135 patients with colorectal cancer, we used immunohistochemistry to investigate the correlation between deficiency in MMR proteins and expression of human leukocyte antigen (HLA) class I molecules, a prerequisite of cytotoxic T-cell-based immunotherapy. Interestingly, MMR protein deficiency was an independent risk factor for the impaired expression of HLA class I molecules (odds ratio (OR)=10.44, 95% confidence interval (CI)=3.15-34.62, p<0.001), suggesting the existence of a putative entity that we have named "adaptive immune escape". Moreover, our results might provide a potential novel biomarker for the selection of patients who would respond to cancer immunotherapies. At the same time, the results suggest that we have to overcome the impaired expression of HLA class I molecules to further improve the cure rate of cancer immunotherapies.
越来越多的证据表明，免疫检查点抑制介导的癌症免疫疗法极大地改善了某些类型癌症的预后。这种方法现在正成为一种标准疗法，与手术、放疗和化疗并驾齐驱。由于抗体药物的成本目前在许多国家已成为一种社会经济负担，癌症免疫治疗中的一个迫切需求是识别能够预测治疗效果的相关生物标志物。最近的研究报告称，错配修复（MMR）蛋白存在遗传性或散发性缺陷的结直肠癌具有高抗原性，检测这些蛋白可能是估计临床反应的一种有前景的方法。在这项对135例结直肠癌患者的研究中，我们使用免疫组织化学来研究MMR蛋白缺陷与人类白细胞抗原（HLA）I类分子表达之间的相关性，HLA I类分子是基于细胞毒性T细胞的免疫治疗的一个先决条件。有趣的是，MMR蛋白缺陷是HLA I类分子表达受损的一个独立危险因素（优势比（OR）=10.44，95%置信区间（CI）=3.15 - 34.62，p<0.001），这表明存在一种我们命名为“适应性免疫逃逸”的假定实体。此外，我们的结果可能为选择对癌症免疫疗法有反应的患者提供一种潜在的新型生物标志物。同时，结果表明我们必须克服HLA I类分子的表达受损，以进一步提高癌症免疫疗法的治愈率。
