CD8型
肿瘤微环境
癌症研究
免疫疗法
细胞因子
背景(考古学)
T细胞受体
免疫系统
T细胞
癌症免疫疗法
免疫学
受体
生物
细胞毒性T细胞
体外
生物化学
古生物学
作者
Christie-Lynn Mortales,Benjamin Dutzar,Jerry Chen,Alex Chen,Justin Huard,Carl Walkey,Ryan Swanson
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2023-05-02
卷期号:11 (7): 1000-1010
标识
DOI:10.1158/2326-6066.cir-22-0304
摘要
Abstract Cytokine engineering has shown promise as a means to create novel immunomodulatory agents or to improve upon the therapeutic potential of natural cytokines. NL-201, a de novo, hyperstable, IL2 receptor alpha (IL2Rα)–independent agonist of the receptors for IL2 and IL15, elicits robust preclinical activity in syngeneic murine cancer models, including those resistant to immune checkpoint inhibitors (ICI). Here, we report that NL-201 monotherapy converts ‘cold’ tumor microenvironments (TME) to immunologically ‘hot’ states by driving pro-inflammatory gene expression, enhancing IFNγ-dependent MHC-I expression, and expanding both T-cell number and clonal diversity. In addition, the combination of NL-201 and anti–PD-1 resulted in complementary antitumor activity in the immunologically ‘cold’ and ICI resistant B16F10, EMT6, and Renca syngeneic models. In the B16F10 model, treatment with NL-201 plus anti–PD-1 increased the abundance of CD4+ and CD8+ effector T cells in the TME. These findings reveal an important mechanistic basis for the antitumor activity of NL-201 both as a monotherapy and in combination with PD-1 antagonists, and provide further context for the role of IL2Rα-based signaling in ICI-resistant tumors.
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