Bénigni Paolo, Guénolé Morgan, Bonsang Benjamin, Marcorelles Pascale, Schick Ulrike, Uguen Arnaud
Departments of Pathology.
Oncology and Radiotherapy, CHRU Brest, Brest.
Appl Immunohistochem Mol Morphol. 2020 Jan;28(1):17-22. doi: 10.1097/PAI.0000000000000792.
Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis have revolutionized the treatment of patients with Merkel cell carcinoma (MCC). To date, no biomarker conditions access to these ICIs in MCC. We compared the tumor microenvironment of PD-L1 and PD-L1 areas in a case series of MCC searching for foci evocative of PD-1/PD-L1 adaptive immune resistance. Among 58 tumors studied on digitalized serial tissue sections, 11 (19%) were concluded as "PD-L1 tumors" [≥1% positive tumor cells (TCs) using PD-L1 immunohistochemistry in the whole tumor slide]. In addition, among the remaining 47 (81%) "PD-L1 tumors," we nevertheless also identified "PD-L1 FOV" (ie, "field of view" of about 3 mm² containing ≥1% positive TCs) in 22 (38%) additional tumors. Comparison between paired "PD-L1 field of view (FOV)" and "PD-L1 FOV" within tumors, and between "PD-L1 tumors" and "PD-L1 tumors", revealed correlations between PD-L1 positivity and the abundance of tumor-infiltrating leukocytes, arguing for areas of PD-1/PD-L1-related adaptive immune resistance at least in some foci of "PD-L1 tumors" and also in "PD-L1 tumors." Tumor heterogeneity consists in a challenge searching for biomarkers able to predict the response/nonresponse to ICIs. Progress in digital pathology and multiplex immunolabeling may permit to overcome this challenge by better analyzing the interactions between TCs and immune and nonimmune non-TCs in the same tissue section. This approach of tumor heterogeneity may contribute to elucidate and to predict why some patients respond impressively to ICIs, whereas others do not.
靶向程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡配体1（PD-L1）轴的免疫检查点抑制剂（ICI）彻底改变了默克尔细胞癌（MCC）患者的治疗方式。迄今为止，在MCC中尚无生物标志物可作为使用这些ICI的依据。我们在一组MCC病例系列中比较了PD-L1阳性和阴性区域的肿瘤微环境，以寻找提示PD-1/PD-L1适应性免疫抵抗的病灶。在对数字化连续组织切片研究的58个肿瘤中，11个（19%）被判定为“PD-L1肿瘤”[在整个肿瘤切片中使用PD-L1免疫组化检测，阳性肿瘤细胞（TC）≥1%]。此外，在其余47个（81%）“PD-L1阴性肿瘤”中，我们在另外22个（38%）肿瘤中也发现了“PD-L1视野（FOV）”（即约3mm²的“视野”，其中TC阳性≥1%）。肿瘤内配对的“PD-L1视野（FOV）”与“PD-L1阴性FOV”之间，以及“PD-L1肿瘤”与“PD-L1阴性肿瘤”之间的比较显示，PD-L1阳性与肿瘤浸润白细胞数量之间存在相关性，这表明至少在一些“PD-L1肿瘤”病灶以及“PD-L1阴性肿瘤”中存在与PD-1/PD-L1相关的适应性免疫抵抗区域。肿瘤异质性是寻找能够预测对ICI反应/无反应的生物标志物的一个挑战。数字病理学和多重免疫标记技术的进展可能有助于通过在同一组织切片中更好地分析TC与免疫及非免疫非TC之间的相互作用来克服这一挑战。这种肿瘤异质性的研究方法可能有助于阐明并预测为何有些患者对ICI反应显著，而另一些患者则不然。
