细胞毒性T细胞
尼罗替尼
医学
封锁
癌症研究
白血病
免疫学
嵌合抗原受体
免疫检查点
T细胞
免疫系统
免疫疗法
生物
内科学
伊马替尼
受体
髓系白血病
体外
生物化学
作者
Sean I. Tracy,Hrishi Venkatesh,Can Hekim,Lynn Heltemes-Harris,Todd P. Knutson,Veronika Bachanová,Michael A. Farrar
出处
期刊:Blood
[American Society of Hematology]
日期:2022-03-11
被引量:10
标识
DOI:10.1182/blood.2021015341
摘要
Patients with acute lymphoblastic leukemia have experienced significantly improved outcomes due to the advent of chimeric antigen receptor T-cells and bispecific T-cell engagers, although a proportion of patients still relapse despite these advances. T-cell exhaustion has been recently suggested to be an important driver of relapse in these patients. Indeed, phenotypic exhaustion of CD4+ T-cells is predictive of relapse and poor overall survival in B-ALL. Thus, therapies that counter T-cell exhaustion, such as immune checkpoint blockade, may improve leukemia immunosurveillance and prevent relapse. Here, we used a murine model of Ph+ B-ALL as well as human bone marrow biopsy samples to assess the fundamental nature of CD4+ T-cell exhaustion and the preclinical therapeutic potential for combining anti-PD-L1 based checkpoint blockade with tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein. scRNA-seq analysis revealed that B-ALL induces a unique subset of CD4+ T-cells with both cytotoxic and helper functions. Combination treatment with the tyrosine kinase inhibitor nilotinib and anti-PD-L1 dramatically improves long-term survival of leukemic mice. Depletion of CD4+ T-cells prior to therapy completely abrogates the survival benefit, implicating CD4+ T-cells as key drivers of the protective anti-leukemia immune response. Indeed, treatment with anti-PD-L1 leads to clonal expansion of leukemia-specific CD4+ T-cells with the afore-mentioned helper/cytotoxic phenotype, as well as reduced expression of exhaustion markers. These findings support efforts to utilize PD1/PD-L1 checkpoint blockade in clinical trials and highlight the importance of CD4+ T-cell dysfunction in limiting the endogenous anti-leukemia response.
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