Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Center for Cellular Immunotherapies, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Eur J Immunol. 2022 Jan;52(1):96-108. doi: 10.1002/eji.202149329. Epub 2021 Sep 18.
The detection of tumor-specific T cells in solid tumors is integral to interrogate endogenous antitumor responses and to advance downstream therapeutic applications. Multiple biomarkers are reported to identify endogenous tumor-specific tumor-infiltrating lymphocytes (TILs), namely CD137, PD-1, CD103, and CD39; however, a direct comparison of these molecules has yet to be performed. We evaluated these biomarkers in primary human ovarian tumor samples using single-cell mass cytometry to compare their relative phenotypic profiles, and examined their response to autologous tumor cells ex vivo. PD-1 , CD103 , and CD39 TILs all contain a CD137 cell subset, while CD137 TILs highly co-express the aforementioned markers. CD137 TILs exhibit the highest expression of cytotoxic effector molecules compared to PD-1 , CD103 , or CD39 TILs. Removal of CD137 cells from PD-1 , CD103 , or CD39 TILs diminish their IFN-γ secretion in response to autologous tumor cell stimulation, while CD137 TILs maintain high HLA-dependent IFN-γ secretion. CD137 TILs exhibited an exhausted phenotype but with CD28 co-expression, suggesting possible receptiveness to reinvigoration via immune checkpoint blockade. Together, our findings demonstrate that the antitumor abilities of PD-1 , CD103 , and CD39 TILs are mainly derived from a subset of CD137-expressing TILs, implicating CD137 as a more selective biomarker for naturally occurring tumor-specific TILs.
在实体瘤中检测肿瘤特异性 T 细胞对于探究内源性抗肿瘤反应并推进下游治疗应用至关重要。已有多种生物标志物被报道可用于鉴定内源性肿瘤特异性肿瘤浸润淋巴细胞(TILs),包括 CD137、PD-1、CD103 和 CD39;然而,这些分子之间的直接比较尚未进行。我们使用单细胞质谱流式细胞术评估了这些生物标志物在原发性人卵巢肿瘤样本中的表达,以比较它们相对的表型特征,并研究它们对外源肿瘤细胞的反应。PD-1、CD103 和 CD39 TILs 均包含 CD137 细胞亚群,而 CD137 TILs 高度共表达上述标志物。与 PD-1、CD103 或 CD39 TILs 相比,CD137 TILs 表达更高水平的细胞毒性效应分子。从 PD-1、CD103 或 CD39 TILs 中去除 CD137 细胞会降低其对外源肿瘤细胞刺激的 IFN-γ 分泌,而 CD137 TILs 则保持高水平的 HLA 依赖性 IFN-γ 分泌。CD137 TILs 表现出耗竭表型,但伴有 CD28 共表达,提示其可能通过免疫检查点阻断重新激活。综上所述,我们的研究结果表明,PD-1、CD103 和 CD39 TILs 的抗肿瘤能力主要源自 CD137 表达 TILs 的一个亚群,表明 CD137 是自然发生的肿瘤特异性 TILs 的更具选择性的生物标志物。
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