Human Cancers Express TRAILshort, a Dominant Negative TRAIL Splice Variant, Which Impairs Immune Effector Cell Killing of Tumor Cells.
Human Cancers Express TRAILshort, a Dominant Negative TRAIL Splice Variant, Which Impairs Immune Effector Cell Killing of Tumor Cells.
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DOI：
10.1158/1078-0432.ccr-20-0251
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发表时间：
2020-11-01
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影响因子：
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通讯作者：
Badley AD
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文献类型：
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作者：
Aboulnasr F;Krogman A;Graham RP;Cummins NW;Misra A;Garcia-Rivera E;Anderson JR;Natesampillai S;Kogan N;Aravamudan M;Nie Z;Chung TDY;Buick R;Feldman AL;King RL;Novak AJ;Ansell SM;Kenderian S;Badley AD
转化癌症机制和治疗。免疫细胞表达的 TNF 相关凋亡诱导配体 (TRAIL) 有助于抗肿瘤免疫。 TRAIL 的一种天然剪接变体称为 TRAILshort，可拮抗 TRAIL 依赖性细胞杀伤作用。目前尚不清楚肿瘤细胞是否表达 TRAILshort 以及它是否影响抗肿瘤免疫。我们使用公正的信息学方法来识别原发性人类癌症中的 TRAILshort 表达，并通过免疫组织化学 (IHC) 和原位杂交 (ISH) 验证这些结果。 TRAILshort 特异性单克隆抗体用于确定 TRAILshort 对肿瘤细胞对 TRAIL 敏感性的影响，以及对自体原发性肿瘤的免疫效应细胞依赖性杀伤的影响。通过 RNAseq 和 IHC 分析，多达 40% 的原发性人类肿瘤表达 TRAILshort。通过 ISH，TRAILshort 表达存在于肿瘤细胞中，而不是旁观细胞中。 TRAIL 短抑制可增强癌细胞系对体外和免疫缺陷异种移植小鼠模型中 TRAIL 依赖性杀伤的敏感性。与不存在 TRAILshort 抗体相比，从 B 细胞恶性肿瘤患者中分离的免疫效应细胞在存在 TRAILshort 抗体的情况下杀死了更多的自体肿瘤细胞（P<0.05）。这些结果鉴定了人类原发性恶性肿瘤中的 TRAILshort，并表明 TRAILshort 阻断可以增强自体免疫效应细胞的效应功能。激活后，免疫效应细胞表达 TRAIL，但由于 TRAILshort 的存在，无法杀死表达 TRAIL 受体 1 或 2 的肿瘤细胞。当 TRAILshort 被特定抗体中和时，免疫效应细胞对肿瘤细胞的杀伤力增强。
Translational Cancer mechanisms and therapy. TNF-related apoptosis inducing ligand (TRAIL) expression by immune cells contributes to anti-tumor immunity. A naturally occurring splice variant of TRAIL, called TRAILshort, antagonizes TRAIL-dependent cell killing. It is unknown whether tumor cells express TRAILshort and if it impacts anti-tumor immunity. We used an unbiased informatics approach to identify TRAILshort expression in primary human cancers, and validated those results with immunohistochemistry (IHC) and in situ hybridization (ISH). TRAILshort specific monoclonal antibodies were used to determine the effect of TRAILshort on tumor cell sensitivity to TRAIL, and to immune effector cell dependent killing of autologous primary tumors. As many as 40% of primary human tumors express TRAILshort by both RNAseq and IHC analysis. By ISH, TRAILshort expression is present in tumor cells and not bystander cells. TRAILshort inhibition enhances cancer cell lines sensitivity to TRAIL dependent killing both in vitro and in immunodeficient xenograft mouse models. Immune effector cells isolated from patients with B cell malignancies killed more autologous tumor cells in the presence compared to the absence of TRAILshort antibody (P<0.05). These results identify TRAILshort in primary human malignancies, and suggest that TRAILshort blockade can augment the effector function of autologous immune effector cells. Following activation, immune effector cells express TRAIL, but are unable to kill TRAIL-receptor 1 or 2 expressing tumor cells, due to the presence of TRAILshort. When TRAILshort is neutralized by a specific antibody, immune effector cell killing of tumor cells is enhanced.