HHLA2, a New Immune Checkpoint Member of the B7 Family, Is Widely Expressed in Human Lung Cancer and Associated with EGFR Mutational Status.
HHLA2, a New Immune Checkpoint Member of the B7 Family, Is Widely Expressed in Human Lung Cancer and Associated with EGFR Mutational Status.
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DOI：
10.1158/1078-0432.ccr-15-3071
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发表时间：
2017-02-01
期刊：
影响因子：
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通讯作者：
Zang X
中科院分区：
文献类型：
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作者：
Cheng H;Janakiram M;Borczuk A;Lin J;Qiu W;Liu H;Chinai JM;Halmos B;Perez-Soler R;Zang X
针对B7/CD28家族成员（包括PD-1、PD-L1和CTLA-4）的抗体进行免疫治疗已经改变了非小细胞肺癌（NSCLC）的治疗模式，改善了临床结果。HHLA2是新发现的家族成员。通过调节t细胞功能，HHLA2可能参与肿瘤免疫抑制，从而成为肿瘤免疫治疗的新靶点。目前对其在非小细胞肺癌中的表达谱和临床意义的研究信息有限。我们利用679例NSCLC肿瘤组织构建的组织微阵列，对hhla2特异性抗体（克隆566.1）进行免疫组化，其中发现组392例，验证组287例。我们还研究了这些患者的临床病理特征。总体而言，HHLA2未在大多数正常肺组织中检测到，但在66%的不同亚型的NSCLC中表达。特别是，EGFR突变的NSCLC在发现组（EGFR vs. WT: 76% vs. 53%， P=0.01）和验证组（89% vs. 69%， P=0.01）中与较高的肿瘤HHLA2表达显著相关。在其中一个队列中，HHLA2在肺腺癌中的表达高于鳞状和大细胞组织学，非西班牙裔白人与西班牙裔，以及肿瘤浸润淋巴细胞（TIL）密度高的肿瘤。在多变量分析中，EGFR突变状态和高TIL强度与肺腺癌中HHLA2表达独立相关。HHLA2在NSCLC中广泛表达，在肺腺癌中与EGFR突变和高TILs相关。它是肺癌免疫治疗的潜在新靶点。
Immunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non-small-cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC. We performed immunohistochemistry with an HHLA2-specific antibody (clone 566.1) using tissue microarrays constructed from 679 NSCLC tumor tissues, including 392 cases in the discovery set and 287 cases in the validation cohort. We also studied clinico-pathological characteristics of these patients. Overall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR–mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery (EGFR vs. WT: 76% vs. 53%, P=0.01) and validation cohorts (89% vs. 69%, P=0.01). In one of the two cohorts, HHLA2 expression was higher in lung adenocarcinoma as compared to squamous and large cell histology, non-Hispanic White vs. Hispanics, and tumors with high tumor infiltrating lymphocyte (TIL) density. In the multivariate analysis, EGFR mutation status and high TIL intensity were independently associated with HHLA2 expression in lung adenocarcinoma. HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. It is potentially a novel target for lung cancer immunotherapy.