Kassardjian Ari, Moatamed Neda A
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA Los Angeles 90095-1732, California, USA.
Int J Clin Exp Pathol. 2021 Oct 15;14(10):1038-1047. eCollection 2021.
Immune checkpoint inhibitors have a significant role in oncology. One of these immune checkpoints is cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Inhibition of the CTLA-4 pathway has already led to the FDA approval of Ipilimumab (anti-CTLA-4), a targeted therapy for melanoma and other malignancies. CD137 is an inducible, costimulatory receptor of the tissue-necrosis-factor-receptor superfamily expressed on the activated immune cells. Clinical trials have also been set for anti-CD137 in several malignancies. We assessed CTLA-4 and CD137 expression on a tissue microarray (TMA) comprising of 99 core tissues which included normal, non-neoplastic, and neoplastic cervical lesions. When detected as strong granular cytoplasmic reaction in the epithelial cells, CTLA-4 expression was scored as positive. For CD137, the results were recorded based on the presence or absence of staining reaction on the cell membranes of the lymphoplasmacytic infiltrates. Overall, CTLA-4 was positive in 30% (30/100) of the cervical malignancies. Sub-categorically, 20% of invasive endocervical adenocarcinomas, 63% of adenosquamous carcinomas, and 31% of squamous cell carcinomas were positive for CTLA-4 with a tendency toward lower grade squamous cell carcinomas (SCCs). CD137 was positive in 100% lymphoplasmacytic infiltrates of endocervical adenocarcinomas, 90.5% of SCCs, and 87.5% of adenosquamous carcinomas. This study has found a significant expression of CTLA-4 in cervical cancer cells and CD137 positivity of lymphoplasmacytic infiltrates with potential for future targeted immunotherapy.
免疫检查点抑制剂在肿瘤学中发挥着重要作用。其中一个免疫检查点是细胞毒性T淋巴细胞相关蛋白4（CTLA-4）。抑制CTLA-4通路已促使美国食品药品监督管理局（FDA）批准了伊匹单抗（抗CTLA-4），这是一种用于治疗黑色素瘤和其他恶性肿瘤的靶向疗法。CD137是一种可诱导的共刺激受体，属于组织坏死因子受体超家族，在活化的免疫细胞上表达。针对抗CD137的临床试验也已在多种恶性肿瘤中开展。我们评估了99个核心组织组成的组织微阵列（TMA）上CTLA-4和CD137的表达情况，这些核心组织包括正常、非肿瘤性和肿瘤性宫颈病变。当在上皮细胞中检测到强颗粒状细胞质反应时，CTLA-4表达被评为阳性。对于CD137，根据淋巴浆细胞浸润细胞膜上染色反应的有无记录结果。总体而言，30%（30/100）的宫颈恶性肿瘤中CTLA-4呈阳性。细分来看，20%的浸润性宫颈腺癌、63%的腺鳞癌和31%的鳞状细胞癌CTLA-4呈阳性，低级别鳞状细胞癌（SCC）有更低表达的趋势。在宫颈腺癌的100%淋巴浆细胞浸润、90.5%的SCC和87.5%的腺鳞癌中，CD137呈阳性。本研究发现CTLA-4在宫颈癌细胞中有显著表达，淋巴浆细胞浸润呈CD137阳性，具有未来靶向免疫治疗的潜力。
