未分化的单核细胞可以负载肿瘤抗原（Ag）并经静脉注射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转移到残留的脾树突状细胞（DC），从而刺激强烈的CD8+ CTL反应。在本研究中，我们调查了单核细胞疫苗与CDX-301，一种展宽树突状细胞的细胞因子，即类似Fms酪氨酸激酶3受体（Flt3L），能否提高抗编程性细胞死亡（anti-PD-1）免疫检查点阻滞的抗肿瘤效果。我们发现，在C57BL/6小鼠中，在单核细胞疫苗之前给予Flt3L可扩大脾部DC超过40倍，并使循环Ag特异性T细胞数量翻倍。此外，与单独进行的检查点阻滞相比，OVA-单核细胞疫苗与anti-PD-1、anti-PD-L1或anti-CTLA-4的联合使用抑制了皮下B16/F10-OVA肿瘤的生长程度更大。当一起使用时，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肿瘤生长方面改善了Flt3L和anti-PD-1的抗肿瘤效果。据我们所知，这是首次证明癌症疫苗策略和Flt3L可以提高anti-PD-1的抗肿瘤效果。本研究所呈现的发现进一步证明了单核细胞疫苗如何在进入临床试验时改善Flt3L和免疫检查点阻滞，有待进一步研究。版权所有©2023 Wolters Kluwer Health公司。保留所有权利。

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.Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.