B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity
B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity
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DOI：
10.1158/1078-0432.ccr-17-2852
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发表时间：
2018-06-01
影响因子：
11.5
通讯作者：
Nakagawa, Kazuhiko
中科院分区：
文献类型：
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作者：
Yonesaka, Kimio;Haratani, Koji;Nakagawa, Kazuhiko
目的：抗程序性死亡-1(PD-1)免疫治疗可提高非小细胞肺癌(NSCLC)的生存率，但某些病例难以治疗，因此需要替代治疗策略。B7-H3是一种免疫检查点分子，在多种恶性肿瘤中都有表达。据我们所知，这项研究首次评估了抗PD-1治疗的NSCLC中B7-H3的表达以及抗PD-1治疗和B7-H3靶向治疗的联合治疗潜力。实验设计：应用免疫组织化学方法检测82例非小细胞肺癌患者B7-H3的表达，并分析其与抗PD-1治疗和CD8(+)肿瘤浸润性淋巴细胞(TILs)的反应性的关系。采用小鼠同基因肿瘤模型，评价抗B7-H3和抗程序性死亡配体-1(PD-L1)双抗体治疗的抗肿瘤效果。结果：74%的NSCLC中B7-H3表达明显，且与抗PD-1免疫治疗无反应密切相关。少量CD8(+)TIL作为PD-L1肿瘤比例评分小于50%的亚群，而CD8(+)TIL在不表达B7-H3的肿瘤中仍然丰富。抗B7-H3抗体阻断后，CD8(+)TIL数量增加，效应功能恢复，显示抗肿瘤作用。CD8(+)T细胞的耗竭抵消了B7-H3阻断诱导的抗肿瘤作用，提示CD8(+)T细胞是通过CD8(+)T细胞介导的。与单一封闭抗体相比，B7-H3和PD-L1的双重封闭增强了肿瘤细胞的抗肿瘤反应。结论：肿瘤细胞表达的B7-H3有可能避开CD8(+)-T细胞介导的免疫监视。抗B7-H3免疫治疗联合抗PD-1/PD-L1抗体治疗B7-H3表达的非小细胞肺癌是一种很有前途的治疗方法。(C)2018年AACR。
Purpose: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting.Experimental Design: B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (n = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8(+) tumor-infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry.Results: B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8(+) TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8(+) TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8(+) TILs and recovery of effector function. CD8(+) T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8(+) T cells. Compared with a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction.Conclusions: B7-H3 expressed on tumor cells potentially circumvents CD8(+)-T-cell-mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3-expressing NSCLCs. (C) 2018 AACR.