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.

中文翻译：

---

表达树突状细胞生长因子Flt3L的T细胞的过继细胞疗法可驱动抗原表位扩散和抗肿瘤免疫力。

使用基因改造的T细胞受体或嵌合抗原受体T细胞的过继细胞疗法是免疫疗法的新兴形式，其将T细胞重定向至特异性靶向癌症。然而，肿瘤抗原异质性仍然是限制其抗实体癌功效的关键挑战。在这里，我们工程改造T细胞分泌树突状细胞（DC）生长因子Fms样酪氨酸激酶3配体（Flt3L）。与免疫激动剂聚（I：C）和抗4-1BB结合使用时，分泌Flt3L的T细胞扩展了肿瘤内常规的1型DC，并显着提高了宿主DC和T细胞的活化。重要的，在T细胞受体和嵌合抗原受体T细胞疗法的实体瘤模型中，联合疗法可增强对肿瘤生长的抑制作用，并诱导抗原表位向抗原扩散，这些抗原被过继转移的T细胞识别。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的临床问题的有前途的策略。