Systematic analysis of CD39, CD103, CD137, and PD-1 as biomarkers for naturally occurring tumor antigen-specific TILs,European Journal of Immunology

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Systematic analysis of CD39, CD103, CD137, and PD-1 as biomarkers for naturally occurring tumor antigen-specific TILs
European Journal of Immunology ( IF 4.5 ) Pub Date : 2021-09-10 , DOI: 10.1002/eji.202149329
Monika A Eiva _{1,

2,

3} , Dalia K Omran ₁ , Jessica A Chacon ₄ , Daniel J Powell _{1,

2,

3}

Affiliation

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.

中文翻译：

CD39、CD103、CD137 和 PD-1 作为天然肿瘤抗原特异性 TIL 生物标志物的系统分析

实体瘤中肿瘤特异性 T 细胞的检测对于询问内源性抗肿瘤反应和推进下游治疗应用是不可或缺的。据报道，多种生物标志物可识别内源性肿瘤特异性肿瘤浸润淋巴细胞 (TIL)，即 CD137、PD-1、CD103 和 CD39；然而，尚未对这些分子进行直接比较。我们使用单细胞质谱流式细胞术评估了原代人卵巢肿瘤样本中的这些生物标志物，以比较它们的相对表型特征，并检查了它们对离体自体肿瘤细胞的反应。PD-1 ⁺、CD103 ⁺和 CD39 ⁺ TIL 均包含 CD137 ⁺细胞亚群，而 CD137 ⁺TIL 高度共表达上述标记。^{与 PD-1 +}、CD103 ⁺或 CD39 ⁺ TIL 相比， CD137 ⁺ TIL 表现出最高的细胞毒性效应分子表达。从 PD-1 ⁺、CD103 ⁺或 CD39 ⁺ TIL中去除 CD137 ⁺细胞会减少其对自体肿瘤细胞刺激的 IFN-γ 分泌，而 CD137 ⁺ TIL 会维持高 HLA 依赖性 IFN-γ 分泌。CD137 ⁺TIL 表现出疲惫的表型，但与 CD28 共表达，表明可能通过免疫检查点封锁接受重振。总之，我们的研究结果表明，PD-1 ⁺、CD103 ⁺和 CD39 ⁺ TIL 的抗肿瘤能力主要来自表达 CD137 的 TIL 的一个子集，表明 CD137 是天然存在的肿瘤特异性 TIL 的更具选择性的生物标志物。

更新日期：2021-09-10

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