VISTA Regulates the Development of Protective Antitumor Immunity.
VISTA Regulates the Development of Protective Antitumor Immunity.
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DOI：
10.1158/0008-5472.can-13-1506
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发表时间：
2014-04-01
期刊：
影响因子：
11.2
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Le Mercier I;Chen W;Lines JL;Day M;Li J;Sergent P;Noelle RJ;Wang L
T细胞活化的V域IG抑制因子（VISTA）是一种新型的负性检查点配体，其与PD-L1同源并抑制T细胞活化。这项研究证明了VISTA缓解造血细胞负调控和增强保护性抗肿瘤免疫的多种机制。VISTA在骨髓细胞和Foxp 3 + CD 4+调节细胞上高度表达，但在肿瘤微环境（TME）内的肿瘤细胞上不表达。VISTA单克隆抗体（mAb）处理增加了外周中肿瘤特异性T细胞的数量，并增强了TME内肿瘤反应性T细胞的浸润、增殖和效应子功能。VISTA阻断通过减少单核细胞骨髓源性抑制细胞的存在并增加TME内活化DC的存在来改变TME的抑制特征。此外，VISTA阻断损害了抑制功能并减少了肿瘤特异性Foxp 3 + CD 4+调节性T细胞的出现。因此，VISTA单抗作为单一疗法施用显著抑制可移植和诱导型黑素瘤的生长。最初的研究探索了使用VISTA阻断和具有TLR激动剂作为佐剂的基于肽的癌症疫苗的组合方案。VISTA阻断与疫苗协同作用以有效地损害已建立的肿瘤的生长。因此，我们的研究为设计VISTA靶向方法奠定了基础，无论是作为单一疗法还是与其他免疫靶向策略相结合用于癌症免疫治疗。
V-domain Ig suppressor of T cell activation (VISTA) is a novel negative checkpoint ligand that is homologous to PD-L1 and suppresses T cell activation. This study demonstrates the multiple mechanisms whereby VISTA relieves negative regulation by hematopoietic cells and enhances protective anti-tumor immunity. VISTA is highly expressed on myeloid cells and Foxp3+CD4+ regulatory cells, but not on tumor cells within the tumor microenvironment (TME). VISTA monoclonal antibody (mab) treatment increased the number of tumor-specific T cells in the periphery, and enhanced the infiltration, proliferation and effector function of tumor-reactive T cells within the TME. VISTA blockade altered the suppressive feature of the TME, by decreasing the presence of monocytic myeloid-derived suppressor cells and increasing the presence of activated DCs within the TME. In addition, VISTA blockade impaired the suppressive function and reduced the emergence of tumor-specific Foxp3+CD4+ regulatory T cells. Consequently, VISTA mab administration as a monotherapy significantly suppressed the growth of both transplantable and inducible melanoma. Initial studies explored a combinatorial regimen using VISTA blockade and a peptide-based cancer vaccine with TLR agonists as adjuvants. VISTA blockade synergized with the vaccine to effectively impair the growth of established tumors. Our study therefore establishes a foundation for designing VISTA-targeted approaches either as a monotherapy or in combination with additional immune-targeted strategies for cancer immunotherapy.