CDK4/6 inhibition promotes immune infiltration in ovarian cancer and synergizes with PD-1 blockade in a B cell-dependent manner
CDK4/6 inhibition promotes immune infiltration in ovarian cancer and synergizes with PD-1 blockade in a B cell-dependent manner
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CDK4/6 抑制促进卵巢癌中的免疫浸润，并以 B 细胞依赖性方式与 PD-1 阻断产生协同作用
DOI：
10.7150/thno.44871
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Chen, Bi-Liang
中科院分区：
文献类型：
--
作者：
Zhang, Qian-Feng;Li, Jia;Chen, Bi-Liang
近十年来，肿瘤免疫治疗领域取得了长足的进步。然而，免疫检查点阻断（ICB）对卵巢癌的治疗效果仍然有限。最近，已报道细胞周期蛋白依赖性激酶4和6（CDK 4/6 i）的抑制剂在临床前模型中增强抗肿瘤免疫。CDK 4/6 i和ICB的联合使用可能是有益的，但CDK 4/6 i对肿瘤免疫微环境的影响以及它们是否能与ICB协同治疗卵巢癌仍是未知的：在这项研究中，我们首先评估了abemaciclib（FDA批准的CDK 4/6 i）在同基因小鼠卵巢癌模型中的抗肿瘤疗效。免疫组化、免疫荧光和流式细胞术检测肿瘤浸润淋巴细胞的数量、比例和活性。通过PCR阵列分析和细胞因子抗体阵列检测细胞因子和趋化因子的产生。在体内评价了abemaciclib和抗PD-1联合治疗的疗效，并使用流式细胞术分析了CD 8+和CD 4 + T细胞活性。最后，在体内评估了联合治疗中对CD 8 + T细胞和B细胞的需求，并通过流式细胞术进一步分析了潜在的细胞机制。结果：我们观察到abemaciclib单药治疗可以增强ID 8小鼠卵巢癌模型中的免疫浸润，尤其是CD 8 + T细胞和B细胞浸润。免疫表型分析显示，abemaciclib在肿瘤微环境中诱导了促炎性免疫应答。PCR阵列分析表明在abemaciclib治疗的ID 8肿瘤中存在Th 1极化细胞因子谱。体外研究表明，abemaciclib处理的ID 8细胞分泌更多的CXCL 10和CXCL 13，因此比对照组招募更多的淋巴细胞。与单药治疗相比，联合治疗取得了更好的肿瘤控制，并且与单药治疗相比，CD 8+和CD 4 + T细胞的活性进一步增强。Abemaciclib联合抗PD-1治疗的协同抗肿瘤效应依赖于CD 8 + T细胞和B细胞。结论：CDK 4/6 i联合抗PD-1抗体治疗可提高抗PD-1治疗的疗效，对免疫浸润性差的卵巢癌的治疗有很大的希望。
Great progress has been made in the field of tumor immunotherapy in the past decade. However, the therapeutic effects of immune checkpoint blockade (ICB) against ovarian cancer are still limited. Recently, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6i) has been reported to enhance antitumor immunity in preclinical models. The combined use of CDK4/6i and ICB may be beneficial, but the effects of CDK4/6is on the tumor immune microenvironment and whether they can synergize with ICB in treating ovarian cancer remain unknown.Methods: In this study, we first assessed the antitumor efficacy of abemaciclib, an FDA-approved CDK4/6i, in a syngeneic murine ovarian cancer model. Then, immunohistochemistry, immunofluorescence and flow cytometry were performed to evaluate the number, proportion, and activity of tumor-infiltrating lymphocytes. Cytokine and chemokine production was detected both in vivo and in vitro by PCR array analysis and cytokine antibody arrays. The treatment efficacy of combined abemaciclib and anti-PD-1 therapy was evaluated in vivo, and CD8+ and CD4+ T cell activities were analyzed using flow cytometry. Lastly, the requirement for both CD8+ T cells and B cells in combination treatment was evaluated in vivo, and potential cellular mechanisms were further analyzed by flow cytometry.Results: We observed that abemaciclib monotherapy could enhance immune infiltration, especially CD8+ T cell and B cell infiltration, in the ID8 murine ovarian cancer model. Immunophenotyping analysis showed that abemaciclib induced a proinflammatory immune response in the tumor microenvironment. PCR array analysis suggested the presence of a Th1-polarized cytokine profile in abemaciclib-treated ID8 tumors. In vitro studies showed that abemaciclib-treated ID8 cells secreted more CXCL10 and CXCL13, thus recruiting more lymphocytes than control groups. Combination treatment achieved better tumor control than monotherapy, and the activities of CD8+ and CD4+ T cells were further enhanced when compared with monotherapy. The synergistic antitumor effects of combined abemaciclib and anti-PD-1 therapy depended on both CD8+ T cells and B cells.Conclusion: These findings suggest that combined treatment with CDK4/6i and anti-PD-1 antibody could improve the efficacy of anti-PD-1 therapy and hold great promise for the treatment of poorly immune-infiltrated ovarian cancer.