Immune checkpoint blockade has been used to treat breast cancer, but the clinical responses remain relatively poor. We have used the CRISPR-Cas9 kinome knockout library consisting of 763 kinase genes to identify tumor-intrinsic kinases conferring resistance to anti-PD-1 immune checkpoint blockade. We have identified the CDC42BPB kinase as a potential target to overcome the resistance to anti-PD-1 immune checkpoint blockade immunotherapy. We found that CDC42BPB is highly expressed in breast cancer patients who are non-responsive to immunotherapy. Furthermore, a small-molecule pharmacological inhibitor, BDP5290, which targets CDC42BPB, synergized with anti-PD-1 and enhanced tumor cell killing by promoting T cell proliferation in both and assays. Moreover, anti-PD-1-resistant breast cancer cells showed higher expression of CDC42BPB, and its inhibition rendered the resistant cells more susceptible to T cell killing in the presence of anti-PD-1. We also found that CDC42BPB phosphorylated AURKA, which in turn upregulated PD-L1 through cMYC. Our results have revealed a robust link between tumor-intrinsic kinase and immunotherapy resistance and have provided a rationale for a unique combination therapy of CDC42BPB inhibition and anti-PD-1 immunotherapy for breast cancer.

中文翻译：

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肿瘤固有的 CDC42BPB 赋予乳腺癌抗 PD-1 免疫检查点阻断的抵抗力


免疫检查点阻断已被用于治疗乳腺癌，但临床反应仍然相对较差。我们使用由 763 个激酶基因组成的 CRISPR-Cas9 激酶组敲除文库来鉴定赋予抗 PD-1 免疫检查点阻断抗性的肿瘤内在激酶。我们已确定 CDC42BPB 激酶作为克服抗 PD-1 免疫检查点阻断免疫治疗耐药性的潜在靶点。我们发现 CDC42BPB 在对免疫治疗无反应的乳腺癌患者中高表达。此外，一种以 CDC42BPB 为靶点的小分子药物抑制剂 BDP5290 与抗 PD-1 具有协同作用，并通过促进 T 细胞增殖来增强肿瘤细胞杀伤作用。此外，抗PD-1耐药乳腺癌细胞表现出较高的CDC42BPB表达，其抑制作用使耐药细胞在抗PD-1存在的情况下更容易被T细胞杀死。我们还发现 CDC42BPB 磷酸化 AURKA，进而通过 cMYC 上调 PD-L1。我们的结果揭示了肿瘤内在激酶与免疫治疗耐药性之间的紧密联系，并为乳腺癌的 CDC42BPB 抑制和抗 PD-1 免疫治疗的独特联合疗法提供了理论基础。