期刊
CANCER DISCOVERY
卷 9, 期 9, 页码 1192-1207出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-18-1356
关键词
-
类别
资金
- Myeloproliferative Neoplasms Research Foundation
- Leukemia & Lymphoma Society
- Parker Institute for Cancer Immunotherapy
- NCI P30 Cancer Center Support Grant [P30 CA196521]
Somatic frameshift mutations in the calreticulin (CALR) gene are key drivers of cellular transformation in myeloproliferative neoplasms (MPN). All patients carrying these mutations (CALR(+) MPN) share an identical sequence in the C-terminus of the mutated CALR protein (mut-CALR), with the potential for utility as a shared neoantigen. Here, we demonstrate that although a subset of patients with CALR(+) MPN develop specific T-cell responses against the mut-CALR C-terminus, PD-1 or CTLA4 expression abrogates the full complement of responses. Significantly, blockade of PD-1 and CLTA4 ex vivo by mAbs and of PD-1 in vivo by pembrolizumab administration restores mut-CALR-specific T-cell immunity in some patients with CALR(+) MPN. Moreover, mut-CALR elicits antigen-specific responses from both CD4(+) and CD8(+) T cells, confirming its broad applicability as an immunogen. Collectively, these results establish mut-CALR as a shared, MPN-specific neoantigen and inform the design of novel immunotherapies targeting mut-CALR. SIGNIFICANCE Current treatment modalities for MPN are not effective in eliminating malignant cells. Here, we show that mutations in the CALR gene, which drive transformation in MPN, elicit T-cell responses that can be further enhanced by checkpoint blockade, suggesting immunotherapies could be employed to eliminate CALR(+) malignant cells in MPN.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据