van Dinther Dieke, Lopez Venegas Miguel, Veninga Henrike, Olesek Katarzyna, Hoogterp Leoni, Revet Mirjam, Ambrosini Martino, Kalay Hakan, Stöckl Johannes, van Kooyk Yvette, den Haan Joke M M
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
DC4U B.V., De Corridor 21E, 3621 ZA Breukelen, The Netherlands.
Cancers (Basel). 2019 Feb 5;11(2):183. doi: 10.3390/cancers11020183.
The lack of tumor-reactive T cells is one reason why immune checkpoint inhibitor therapies still fail in a significant proportion of melanoma patients. A vaccination that induces melanoma-specific T cells could potentially enhance the efficacy of immune checkpoint inhibitors. Here, we describe a vaccination strategy in which melanoma antigens are targeted to mouse and human CD169 and thereby induce strong melanoma antigen-specific T cell responses. CD169 is a sialic acid receptor expressed on a subset of mouse splenic macrophages that captures antigen from the blood and transfers it to dendritic cells (DCs). In human and mouse spleen, we detected CD169⁺ cells at an equivalent location using immunofluorescence microscopy. Immunization with melanoma antigens conjugated to antibodies (Abs) specific for mouse CD169 efficiently induced gp100 and Trp2-specific T cell responses in mice. In HLA-A2.1 transgenic mice targeting of the human MART-1 peptide to CD169 induced strong MART-1-specific HLA-A2.1-restricted T cell responses. Human gp100 peptide conjugated to Abs specific for human CD169 bound to CD169-expressing monocyte-derived DCs (MoDCs) and resulted in activation of gp100-specific T cells. Together, these data indicate that Ab-mediated antigen targeting to CD169 is a potential strategy for the induction of melanoma-specific T cell responses in mice and in humans.
肿瘤反应性T细胞的缺乏是免疫检查点抑制剂疗法在相当一部分黑色素瘤患者中仍然失败的原因之一。一种能诱导黑色素瘤特异性T细胞的疫苗可能会增强免疫检查点抑制剂的疗效。在此，我们描述了一种疫苗接种策略，其中黑色素瘤抗原靶向小鼠和人类的CD169，从而诱导强烈的黑色素瘤抗原特异性T细胞反应。CD169是一种唾液酸受体，表达于小鼠脾脏巨噬细胞的一个亚群上，该亚群可从血液中捕获抗原并将其传递给树突状细胞（DCs）。在人和小鼠的脾脏中，我们使用免疫荧光显微镜在相同位置检测到了CD169⁺细胞。用与小鼠CD169特异性抗体（Abs）偶联的黑色素瘤抗原进行免疫接种，可有效诱导小鼠产生gp100和Trp2特异性T细胞反应。在HLA - A2.1转基因小鼠中，将人类MART - 1肽靶向CD169可诱导强烈的MART - 1特异性HLA - A2.1限制性T细胞反应。与人类CD169特异性抗体偶联的人类gp100肽与表达CD169的单核细胞衍生树突状细胞（MoDCs）结合，并导致gp100特异性T细胞的激活。总之，这些数据表明，抗体介导的抗原靶向CD169是在小鼠和人类中诱导黑色素瘤特异性T细胞反应的一种潜在策略。
