Immunohistochemical Analysis of PD-L1 Expression in Canine Malignant Cancers and PD-1 Expression on Lymphocytes in Canine Oral Melanoma.
Immunohistochemical Analysis of PD-L1 Expression in Canine Malignant Cancers and PD-1 Expression on Lymphocytes in Canine Oral Melanoma.
复制标题
DOI：
10.1371/journal.pone.0157176
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Ohashi K
中科院分区：
文献类型：
--
作者：
Maekawa N;Konnai S;Okagawa T;Nishimori A;Ikebuchi R;Izumi Y;Takagi S;Kagawa Y;Nakajima C;Suzuki Y;Kato Y;Murata S;Ohashi K
自发性癌症是狗的常见疾病。其中，一些恶性肿瘤如口腔黑色素瘤、骨肉瘤、血管肉瘤和肥大细胞瘤通常被认为是临床问题，因为尽管它们的发生率很高，但目前对这些癌症的治疗可能并不总是达到令人满意的结果。由于缺乏针对这些癌症的有效全身治疗，研究人员开始研究新的治疗方法，包括免疫治疗。程序性死亡1（PD-1）是一种具有免疫抑制功能的共刺激受体。当其结合其配体PD-配体1（PD-L1）或PD-L2时，T细胞上的PD-1负调节来自T细胞受体的激活信号，导致细胞毒性T淋巴细胞的效应子功能抑制。PD-L1表达异常已在许多人类癌症中报道，并被认为是癌症的免疫逃逸机制。在临床试验中，抗PD-1或抗PD-L1抗体诱导了几种恶性肿瘤的肿瘤消退，包括晚期黑色素瘤、非小细胞肺癌和肾细胞癌。在这项研究中，为了评估PD-1/PD-L1轴作为犬癌症免疫治疗的新型治疗靶点的潜力，对犬的各种恶性癌症中的PD-L1表达进行了免疫组织化学分析。在这里，我们发现狗口腔黑色素瘤，骨肉瘤，血管肉瘤，肥大细胞瘤，乳腺癌，前列腺癌表达PD-L1，而其他一些类型的癌症没有。此外，PD-1在从口腔黑色素瘤获得的肿瘤浸润淋巴细胞上高度表达，表明这种癌症类型中的淋巴细胞可能已经功能耗尽。这些结果强烈鼓励PD-1/PD-L1抑制剂作为针对犬中这些癌症的新型治疗剂的临床应用。
Spontaneous cancers are common diseases in dogs. Among these, some malignant cancers such as oral melanoma, osteosarcoma, hemangiosarcoma, and mast cell tumor are often recognized as clinical problems because, despite their high frequencies, current treatments for these cancers may not always achieve satisfying outcomes. The absence of effective systemic therapies against these cancers leads researchers to investigate novel therapeutic modalities, including immunotherapy. Programmed death 1 (PD-1) is a costimulatory receptor with immunosuppressive function. When it binds its ligands, PD-ligand 1 (PD-L1) or PD-L2, PD-1 on T cells negatively regulates activating signals from the T cell receptor, resulting in the inhibition of the effector function of cytotoxic T lymphocytes. Aberrant PD-L1 expression has been reported in many human cancers and is considered an immune escape mechanism for cancers. In clinical trials, anti-PD-1 or anti-PD-L1 antibodies induced tumor regression for several malignancies, including advanced melanoma, non-small cell lung carcinoma, and renal cell carcinoma. In this study, to assess the potential of the PD-1/PD-L1 axis as a novel therapeutic target for canine cancer immunotherapy, immunohistochemical analysis of PD-L1 expression in various malignant cancers of dogs was performed. Here, we show that dog oral melanoma, osteosarcoma, hemangiosarcoma, mast cell tumor, mammary adenocarcinoma, and prostate adenocarcinoma expressed PD-L1, whereas some other types of cancer did not. In addition, PD-1 was highly expressed on tumor-infiltrating lymphocytes obtained from oral melanoma, showing that lymphocytes in this cancer type might have been functionally exhausted. These results strongly encourage the clinical application of PD-1/PD-L1 inhibitors as novel therapeutic agents against these cancers in dogs.