Immune Co-inhibitory Receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT in Medullary Thyroid Cancers: A Large Cohort Study
Immune Co-inhibitory Receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT in Medullary Thyroid Cancers: A Large Cohort Study
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甲状腺髓样癌中的免疫共抑制受体 PD-1、CTLA-4、TIM-3、LAG-3 和 TIGIT：大型队列研究
DOI：
10.1210/clinem/dgaa701
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发表时间：
2021-01-01
影响因子：
5.8
通讯作者：
Wei, Wen-Jun
中科院分区：
文献类型：
--
作者：
Shi, Xiao;Li, Cui-Wei;Wei, Wen-Jun
内容：程序性细胞死亡蛋白-1（PD-1）、细胞毒性T淋巴细胞抗原4（CTLA-4）、T细胞免疫球蛋白和含粘蛋白结构域的-3（TIM-3）、淋巴细胞活化基因-3（LAG-3）和T细胞免疫球蛋白和ITIM结构域（TIGIT）被认为是主要的免疫共抑制受体（CIR）和癌症治疗中最有前途的免疫靶点，目的：我们的目的是提供第一个证据关于在一个大的MTC patients.Design和Patients队列中的CIR的表达谱和临床意义：总共有200例在我院接受初次手术的MTC患者。免疫组化检测组织芯片中CIR的表达。结合我们之前的程序性细胞死亡配体-1（PD-L1）研究结果，回顾性分析这些蛋白与临床病理和预后的相关性。在96例患者中检测到TIM-3、PD-1、CTLA-4、LAG-3和TIGIT阳性，TIM-3、PD-1和CTLA-4表达呈正相关者分别为48.0%、27例（13.5%）、25例（12.5%）、6例（3.0%）和6例（3.0%）。对数秩检验和多变量考克斯分析均表明TIM-3、CTLA-4表达和PD-1/PD-L1共表达与更差的无结构性复发生存率相关。此外，在随访期间发展为晚期疾病的20例患者中，12例（60%）显示TIM-3阳性，其中6例同时存在中至强PD-1、PD-L1或CTLA-4表达。使用目前最大的这种罕见癌症的TMA队列，我们描绘了MTC中的CIR表达谱，并鉴定了TIM-3，CTLA-4表达，和PD-1/PD-L1共表达作为肿瘤复发的有希望的生物标志物。此外，晚期MTC的一个子集可能具有免疫原性，因此包括TIM-3、PD-1、PD-L1或CTLA-4阻断的单一或联合免疫疗法可能是未来潜在的治疗方法。
Context: Programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin and ITIM domain (TIGIT) are considered major immune co-inhibitory receptors (CIRs) and the most promising immunotherapeutic targets in cancer treatment, but they are largely unexplored in medullary thyroid carcinoma (MTC).Objective: We aimed to provide the first evidence regarding the expression profiles and clinical significance of CIRs in a large cohort of MTC patients.Design and Patients: In total, 200 MTC patients who received initial surgery in our hospital were included. Immunohistochemistry was performed to evaluate CIR expressions in tissue microarrays (TMAs). Combined with the results of our previous programmed cell death ligand-1 (PD-L1) study, clinicopathologic and prognostic correlations of these proteins were retrospectively analyzed.Results: TIM-3, PD-1, CTLA-4, LAG-3, and TIGIT positivity was detected in 96 (48.0%), 27 (13.5%), 25 (12.5%), 6 (3.0%), and 6 (3.0%) patients, respectively, in whom TIM-3, PD-1, and CTLA-4 expressions were positively correlated. Log-rank tests and multivariate Cox analyses both indicated that TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression were associated with worse structural recurrence-free survival. In addition, among 20 patients who developed advanced disease during follow-up, 12 (60%) showed TIM-3 positivity, among whom 6 cases also had concurrent moderate to strong PD-1, PD-L1, or CTLA-4 expression.Conclusions: Using the currently largest TMA cohort of this rare cancer, we delineated the CIR expression profiles in MTC, and identified TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression as promising biomarkers for tumor recurrence. Furthermore, a subset of advanced MTCs are probably immunogenic, for which single or combined immunotherapy including TIM-3, PD-1, PD-L1, or CTLA-4 blockade may be potential therapeutic approaches in the future.