肿瘤细胞治疗研究
英文原题：Tucatinib promotes immune activation and synergizes with programmed cell death-1 and programmed cell death-ligand 1 inhibition in HER2-positive breast cancer.
Tucatinib promotes immune activation and synergizes with programmed cell death-1 and programmed cell death-ligand 1 inhibition in HER2-positive breast cancer.
图卡替尼有利地调节免疫微环境，与α-PD-L1或α-PD-1联合治疗在临床前HER2阳性肿瘤模型中显示出增强的疗效。这些发现为在临床中研究图卡替尼和免疫检查点抑制提供了依据。
程序性细胞死亡-1（PD-1）和程序性细胞死亡配体1（PD-L1）抑制剂在曲妥珠单抗耐药的晚期HER2阳性乳腺癌患者中疗效不佳。Tucatinib是一种强效、选择性的抗HER2酪氨酸激酶抑制剂，在曲妥珠单抗耐药的晚期患者中已证实具有临床获益。我们研究了tucatinib是否能改变肿瘤微环境，以及这是否可用于治疗疗效。
我们利用2种具有免疫能力的HER2阳性小鼠乳腺癌模型（曲妥珠单抗敏感的H2N113；曲妥珠单抗耐药的Fo5）研究了tucatinib的抗肿瘤疗效及其免疫应答的贡献，以及tucatinib联合曲妥珠单抗和PD-1或PD-L1检查点抑制剂的疗效。
在两种模型中，tucatinib均具有统计学显著性的抑制肿瘤生长作用，并表现出剂量依赖性疗效。对接受tucatinib治疗小鼠的TIL（肿瘤浸润淋巴细胞）进行流式细胞术离体分析显示，CD8+效应记忆T细胞的频率增加、增殖增强且效应功能增强。Tucatinib治疗还增加了CD8+PD-1+和CD8+TIM3+ T细胞、CD49+NK 细胞、单核细胞的频率，以及树突状细胞和巨噬细胞上主要组织相容性复合体II类的表达，并减少了髓源性抑制细胞。基因表达分析显示，与免疫激活、I型和II型干扰素反应、适应性免疫反应和抗原受体信号传导相关的通路具有统计学显著性的富集。在体内，与单用tucatinib相比，tucatinib联合α-PD-L1或α-PD-1表现出统计学显著性的疗效增加并改善了小鼠生存。
BACKGROUND: Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy. METHODS: We investigated the antitumor efficacy and contribution of the immune response of tucatinib using 2 immunocompetent, HER2-positive murine breast cancer models (trastuzumab-sensitive H2N113; trastuzumab-resistant Fo5) and the efficacy of tucatinib with trastuzumab and PD-1 or PD-L1 checkpoint inhibitors. RESULTS: In both models, tucatinib statistically significantly inhibited tumor growth and demonstrated dose-dependent efficacy. Ex vivo analysis by flow cytometry of tumor-infiltrating lymphocytes in mice treated with tucatinib showed increased frequency, higher proliferation, and enhanced effector function of CD8+ effector memory T cells. Tucatinib treatment also increased frequency of CD8+PD-1+ and CD8+TIM3+ T cells, CD49+ natural killer cells, monocytes, and major histocompatibility complex II expression on dendritic cells and macrophages and a decrease in myeloid-derived suppressor cells. Gene expression analysis revealed statistically significant enrichment in pathways associated with immune activation, type I and II interferon response, adaptive immune response, and antigen receptor signaling. In vivo, tucatinib and α-PD-L1 or α-PD-1 demonstrated statistically significantly increased efficacy and improved survival of mice compared with tucatinib alone. CONCLUSION: Tucatinib modulates the immune microenvironment favorably, and combination treatment with α-PD-L1 or α-PD-1 demonstrated increased efficacy in preclinical HER2-positive tumor models. These findings provide a rationale for investigation of tucatinib and immune checkpoint inhibition in the clinic.
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