HHLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma
HHLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma
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HHLA2 和 PD-L1 共表达预示透明细胞肾细胞癌患者预后不良
DOI：
10.1136/jitc-2019-000157
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Huang，Hai
中科院分区：
文献类型：
--
作者：
Zhou，Qiang-Hua;Li，Kai-Wen;Huang，Hai
背景肾透明细胞癌（clear cell renal cell carcinoma，ccRCC）是一种免疫原性很强的肿瘤，但目前只有一小部分患者能从免疫治疗中获益，这可能是由于ccRCC免疫微环境的异质性。因此，探索新的免疫治疗或联合治疗对提高治疗效果具有重要意义。HHLA 2是一种新发现的B7家族成员，在许多肿瘤中表达，包括ccRCC。本研究旨在探讨HLA 2/PD-L1共表达对预后的影响及其与肿瘤浸润淋巴细胞（TIL）的关系。方法采用免疫组化方法检测206例训练队列和197例验证队列原发性ccRCC患者癌组织中HHLA 2、PD-L1、CD 8和CD 4的表达水平。结果肾细胞癌组织中HHLA 2的阳性表达率明显高于PD-L1。HHLA 2阳性表达与坏死、微血管浸润、晚期Fuhrman核和TNM分期显著相关，表明两组患者的无进展生存期（PFS）和总生存期（OS）较短。此外，HHLA 2/PD-L1共表达患者的疾病进展和死亡风险最高。此外，HHLA 2/PD-L1共表达与高密度CD 8+和CD 4 + TIL显着相关。值得注意的是，基于HHLA 2/PD-L1共表达和TIL的新免疫分类成功地对PFS和OS进行了分层，尤其是在TIL阳性患者中。结论HHLA 2在ccRCC中的表达高于PD-L1。HHLA 2/PD-L1共表达对ccRCC患者的预后有不良影响;这一发现为将来ccRCC患者的抗HHLA 2和PD-L1阻断联合免疫治疗提供了理论基础。
Background Although clear cell renal cell carcinoma (ccRCC) is well known as a highly immunogenic tumor, only a small subset of patients could benefit from current immunotherapy, which might be due to the heterogeneity of immune microenvironment in ccRCC. So, it is meaningful to explore novel immunotherapy or combination therapy for improving therapeutic efficacy. HHLA2, a newly discovered B7 family member, is prevalently expressed in numerous tumors, including ccRCC. This study aimed to investigate the prognostic impact of HHLA2/PD-L1 co-expression and its relationship with tumor-infiltrating lymphocytes (TILs). Methods The expression levels of HHLA2, PD-L1, CD8, and CD4 in cancer tissues from cases (206 in the training cohort and 197 in the validation cohort) with surgically resectable primary ccRCC were evaluated by immunohistochemistry. Results The positive rates of HHLA2 were much higher than those of PD-L1 in ccRCC tissues. HHLA2-positive expression was significantly associated with necrosis, microvascular invasion, advanced Fuhrman nuclear, and TNM stage and indicated a shorter progression-free survival (PFS) and overall survival (OS) in both cohorts. Moreover, patients with HHLA2/PD-L1 co-expression suffered the highest risk of disease progression and death by a significant margin. Besides, HHLA2/PD-L1 co-expression was significantly associated with a high density of CD8+ and CD4+ TILs. Notably, a new immune classification, based on HHLA2/PD-L1 co-expression and TILs, successfully stratified PFS and OS, especially in patients with TILs positivity. Conclusions The expression of HHLA2 is more frequent than PD-L1 in ccRCC. HHLA2/PD-L1 co-expression had an adverse impact on the prognoses of patients with ccRCC; this finding provides a rationale for combination immunotherapy with anti-HHLA2 and PD-L1 blockage for patients with ccRCC in the future.