Antigen-loaded Monocyte Administration and Flt3 Ligand Augment the Antitumor Efficacy of Immune Checkpoint Blockade in a Murine Melanoma Model.

IF 3.2 4区 医学 Q3 IMMUNOLOGY Journal of Immunotherapy Pub Date : 2023-11-01 Epub Date: 2023-09-20 DOI:10.1097/CJI.0000000000000487
Vincent M D'Anniballe, Min-Nung Huang, Benjamin D Lueck, Lowell T Nicholson, Ian McFatridge, Michael D Gunn
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Abstract

Undifferentiated monocytes can be loaded with tumor antigens (Ag) and administered intravenously to induce antitumor cytotoxic T lymphocyte (CTL) responses. This vaccination strategy exploits an endogenous Ag cross-presentation pathway, where Ag-loaded monocytes (monocyte vaccines) transfer their Ag to resident splenic dendritic cells (DC), which then stimulate robust CD8 + CTL responses. In this study, we investigated whether monocyte vaccination in combination with CDX-301, a DC-expanding cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), could improve the antitumor efficacy of anti-programmed cell death (anti-PD-1) immune checkpoint blockade. We found that Flt3L expanded splenic DC over 40-fold in vivo and doubled the number of circulating Ag-specific T cells when administered before monocyte vaccination in C57BL/6 mice. In addition, OVA-monocyte vaccination combined with either anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), or anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA-4) suppressed subcutaneous B16/F10-OVA tumor growth to a greater extent than checkpoint blockade alone. When administered together, OVA-monocyte vaccination improved the antitumor efficacy of Flt3L and anti-PD-1 in terms of circulating Ag-specific CD8 + T cell frequency and inhibition of subcutaneous B16/F10-OVA tumor growth. To our knowledge, this is the first demonstration that a cancer vaccine strategy and Flt3L can improve the antitumor efficacy of anti-PD-1. The findings presented here warrant further study of how monocyte vaccines can improve Flt3L and immune checkpoint blockade as they enter clinical trials.

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抗原负载的单核细胞给药和Flt3配体增强小鼠黑色素瘤模型中免疫检查点阻断的抗肿瘤效力。
未分化的单核细胞可以负载肿瘤抗原(Ag)并静脉内给药以诱导抗肿瘤细胞毒性T淋巴细胞(CTL)反应。这种疫苗接种策略利用内源性Ag交叉呈递途径,其中负载Ag的单核细胞(单核细胞疫苗)将其Ag转移到驻留的脾树突状细胞(DC),然后刺激强大的CD8+CTL反应。在本研究中,我们研究了单核细胞疫苗接种与CDX-301(一种DC扩增细胞因子Fms样酪氨酸激酶3配体(Flt3L))联合是否可以提高抗程序性细胞死亡(抗PD-1)免疫检查点阻断的抗肿瘤疗效。我们发现,Flt3L在C57BL/6小鼠单核细胞接种前给药时,使脾脏DC在体内扩增了40倍以上,并使循环Ag特异性T细胞的数量增加了一倍。此外,与单独的检查点阻断相比,OVA单核细胞疫苗接种与抗PD-1、抗程序性细胞死亡配体1(抗PD-L1)或抗细胞毒性T淋巴细胞抗原-4(抗CTLA-4)联合在更大程度上抑制皮下B16/F10-OVA肿瘤生长。当同时给药时,OVA单核细胞疫苗在循环Ag特异性CD8+T细胞频率和抑制皮下B16/F10-OVA肿瘤生长方面提高了Flt3L和抗PD-1的抗肿瘤功效。据我们所知,这首次证明癌症疫苗策略和Flt3L可以提高抗PD-1的抗肿瘤效力。本文的发现值得进一步研究单核细胞疫苗在进入临床试验时如何改善Flt3L和免疫检查点阻断。
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来源期刊
Journal of Immunotherapy
Journal of Immunotherapy 医学-免疫学
CiteScore
6.90
自引率
0.00%
发文量
79
审稿时长
6-12 weeks
期刊介绍: Journal of Immunotherapy features rapid publication of articles on immunomodulators, lymphokines, antibodies, cells, and cell products in cancer biology and therapy. Laboratory and preclinical studies, as well as investigative clinical reports, are presented. The journal emphasizes basic mechanisms and methods for the rapid transfer of technology from the laboratory to the clinic. JIT contains full-length articles, review articles, and short communications.
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