Cyclophosphamide and Vinorelbine Activate Stem-Like CD8+ T Cells and Improve Anti-PD-1 Efficacy in Triple-Negative Breast Cancer
Cyclophosphamide and Vinorelbine Activate Stem-Like CD8+ T Cells and Improve Anti-PD-1 Efficacy in Triple-Negative Breast Cancer
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DOI：
10.1158/0008-5472.can-20-1818
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发表时间：
2021-02-01
期刊：
影响因子：
11.2
通讯作者：
Bertolini, Francesco
中科院分区：
文献类型：
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作者：
Falvo, Paolo;Orecchioni, Stefania;Bertolini, Francesco
检查点抑制剂（CI）在许多肿瘤疾病中激发抗癌免疫，尽管仅在一小部分患者中。基于环磷酰胺(C)的单倍体干细胞移植的临床成功表明，这种药物可能会重新协调免疫系统。利用具有不同肿瘤内免疫背景的三阴性乳腺癌（TNBC）模型，我们证明了间歇性C、CI和vinorel滨的联合治疗可以激活抗原呈递细胞（APC），并通过t细胞相关作用消除局部和转移性肿瘤的生长。治疗后对bbbb50 000个肿瘤内免疫细胞的单细胞转录组分析显示，一个基因标记提示由于暴露于有丝分裂原、配体或特异性抗原以及apc -t细胞粘附而引起的变化。这种转录程序也增加了肿瘤内Tcf1（+）干细胞样CD8(+) T细胞，并改变了终末和祖细胞耗尽T细胞之间的平衡，有利于后者。总的来说，我们的数据支持该疗法在TNBC中的临床研究。意义：乳腺癌小鼠模型的联合治疗通过激活抗基因呈递细胞，增强肿瘤内Tcf1（+）干细胞样CD8(+) T细胞，增加祖细胞耗尽CD8thorn T细胞，增加检查点抑制。
Checkpoint inhibitors (CI) instigate anticancer immunity in many neoplastic diseases, albeit only in a fraction of patients. The clinical success of cyclophosphamide (C)-based haploidentical stem-cell transplants indicates that this drug may re-orchestrate the immune system. Using models of triple-negative breast cancer (TNBC) with different intratumoral immune contexture, we demonstrate that a combinatorial therapy of intermittent C, CI, and vinorelbine activates antigen-presenting cells (APC), and abrogates local and metastatic tumor growth by a T-cell-related effect. Single-cell transcriptome analysis of >50,000 intratumoral immune cells after therapy treatment showed a gene signature suggestive of a change resulting from exposure to a mitogen, ligand, or antigen for which it is specific, as well as APC-to-T-cell adhesion. This transcriptional program also increased intratumoral Tcf1(+) stem-like CD8(+) T cells and altered the balance between terminally and progenitor-exhausted T cells favoring the latter. Overall, our data support the clinical investigation of this therapy in TNBC.Significance: Acombinatorial therapy in mouse models of breast cancer increases checkpoint inhibition by activating anti-genpresenting cells, enhancing intratumoral Tcf1(+) stem-like CD8(+) T cells, and increasing progenitor exhausted CD8thorn T cells.