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工程化改造的T细胞促进抗肿瘤免疫
2020-05-20 20:47

澳大利亚彼得·麦克卡勒姆癌症中心Paul A. Beavis和Phillip K. Darcy课题组合作研究发现,表达树突状细胞生长因子Flt3L的T细胞过继细胞疗法可促进抗原表位扩散和抗肿瘤免疫。该项研究成果发表在2020年5月18日出的《自然-免疫学》杂志上。

研究人员工程化改造了T细胞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)。与免疫激动剂poly(I:C)和抗4-1BB联合使用时,分泌Flt3L的T细胞可扩大肿瘤内1型经典DC,并显著增加宿主DC和T细胞的活化。

重要的是,联合疗法可产生增强的肿瘤生长抑制作用,并诱导抗原表位向抗原扩散,这些抗原超出了在T细胞受体和嵌合抗原受体T细胞疗法治疗实体肿瘤模型中,过继转移T细胞所识别的抗原。该研究数据表明,增加内源性DC是克服过继细胞治疗中抗原阴性肿瘤逃逸临床问题的潜在策略。

据了解,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新兴的免疫治疗形式,其将T细胞重定向从而特异性靶向癌症。然而,肿瘤抗原异质性仍然是限制其抗实体癌功效的关键难题。

附:英文原文

Title: Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity

Author: Junyun Lai, Sherly Mardiana, Imran G. House, Kevin Sek, Melissa A. Henderson, Lauren Giuffrida, Amanda X. Y. Chen, Kirsten L. Todd, Emma V. Petley, Jack D. Chan, Emma M. Carrington, Andrew M. Lew, Benjamin J. Solomon, Joseph A. Trapani, Katherine Kedzierska, Maximilien Evrard, Stephin J. Vervoort, Jason Waithman, Phillip K. Darcy, Paul A. Beavis

Issue&Volume: 2020-05-18

Abstract: 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.

DOI: 10.1038/s41590-020-0676-7

Source: https://www.nature.com/articles/s41590-020-0676-7

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:31.25
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex


本期文章:《自然—免疫学》:Online/在线发表

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