Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity
Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity
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DOI：
10.1038/s41590-020-0676-7
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发表时间：
2020-05-18
影响因子：
30.5
通讯作者：
Beavis, Paul A.
中科院分区：
文献类型：
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作者：
Lai, Junyun;Mardiana, Sherly;Beavis, Paul A.
免疫选择是肿瘤抗原变异的基础，也是过继性细胞疗法的主要障碍。 Darcy、Beavis 及其同事使用经过改造的 T 细胞来表达树突状细胞生长因子 Flt3L，以选择宿主内源性适应性免疫反应并控制实验性肿瘤模型。使用基因工程 T 细胞受体或嵌合抗原受体 T 细胞的过继细胞疗法是新兴的免疫疗法形式，可将 T 细胞重新定向到专门针对癌症的目标。然而，肿瘤抗原异质性仍然是限制其对抗实体癌功效的关键挑战。在这里，我们对 T 细胞进行了改造，使其分泌树突状细胞 (DC) 生长因子 Fms 样酪氨酸激酶 3 配体 (Flt3L)。当与免疫激动剂 Poly (I:C) 和抗 4-1BB 结合时，分泌 Flt3L 的 T 细胞可扩增瘤内常规 1 型 DC，并显着增加宿主 DC 和 T 细胞的活化。重要的是，在T细胞受体和嵌合抗原受体T细胞治疗的实体瘤模型中，联合治疗增强了对肿瘤生长的抑制，并诱导表位向超出过继转移T细胞识别范围的抗原扩散。我们的数据表明，增加内源性 DC 是克服过继细胞治疗后抗原阴性肿瘤逃逸临床问题的一种有前途的策略。
Immunoselection underpins tumor antigenic variability and is a key impediment to adoptive cell therapies. Darcy, Beavis and colleagues use T cells engineered to express the dendritic cell growth factor Flt3L to co-opt the host endogenous adaptive immune response and control experimental tumor models.Adoptive cell therapies using genetically engineered T cell receptor or chimeric antigen receptor T cells are emerging forms of immunotherapy that redirect T cells to specifically target cancer. However, tumor antigen heterogeneity remains a key challenge limiting their efficacy against solid cancers. Here, we engineered T cells to secrete the dendritic cell (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L-secreting T cells expanded intratumoral conventional type 1 DCs and substantially increased host DC and T cell activation when combined with immune agonists poly (I:C) and anti-4-1BB. Importantly, combination therapy led to enhanced inhibition of tumor growth and the induction of epitope spreading towards antigens beyond those recognized by adoptively transferred T cells in solid tumor models of T cell receptor and chimeric antigen receptor T cell therapy. Our data suggest that augmenting endogenous DCs is a promising strategy to overcome the clinical problem of antigen-negative tumor escape following adoptive cell therapy.