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肿瘤相关巨噬细胞通过抗原呈递推动T细胞从前体衰竭状态向终末衰竭转变
作者:小柯机器人 发布时间:2024/12/26 17:11:00

美国杜克大学Peter E. Fecci研究组发现,肿瘤相关巨噬细胞通过抗原呈递推动T细胞,从前体衰竭状态向终末衰竭转变。这一研究成果于2024年12月25日在线发表在国际学术期刊《免疫》上。

研究人员表示,Tex_term仍保留抗肿瘤细胞毒功能,而干细胞样的Tex_prog的频率则更能反映免疫治疗的反应性。

研究人员考察了调控T细胞,向终末衰竭转变的肿瘤内细胞相互作用。研究人员定义了一种度量标准,反映肿瘤内前体衰竭到终末衰竭的比例(PETER),并发现该比例随着固体癌症的肿瘤进展而下降。

对胶质母细胞瘤(GBM)中前体衰竭T细胞(Tex_prog),和终末衰竭的T细胞(Tex_term)的单细胞分析揭示,随着时间推移,Tex_prog细胞的丧失不成比例地加剧,衰竭主要集中在肿瘤特异性T细胞亚群中,且特异性抗原的暴露是获得Tex_term表型的必要条件。

肿瘤相关巨噬细胞(TAM),而非肿瘤细胞,是主要的抗原暴露来源,并驱动Tex_prog向Tex_term的转变。TAM的去除在多个肿瘤模型中增加了Tex_prog细胞的频率,提高了PETER,并促进了对αPD1免疫疗法的反应。因此,靶向TAM-T细胞相互作用,可能进一步促进检查点抑制剂的治疗反应。

附:英文原文

Title: Antigen presentation by tumor-associated macrophages drives T cells from a progenitor exhaustion state to terminal exhaustion

Author: Jessica Waibl Polania, Alexandra Hoyt-Miggelbrink, William H. Tomaszewski, Lucas P. Wachsmuth, Selena J. Lorrey, Daniel S. Wilkinson, Emily Lerner, Karolina Woroniecka, John B. Finlay, Katayoun Ayasoufi, Peter E. Fecci

Issue&Volume: 2024-12-25

Abstract: Whereas terminally exhausted T (Tex_term) cells retain anti-tumor cytotoxic functions, the frequencies of stem-like progenitor-exhausted T (Tex_prog) cells better reflect immunotherapeutic responsivity. Here, we examined the intratumoral cellular interactions that govern the transition to terminal T cell exhaustion. We defined a metric reflecting the intratumoral progenitor exhaustion-to-terminal exhaustion ratio (PETER), which decreased with tumor progression in solid cancers. Single-cell analyses of Tex_prog cells and Tex_term cells in glioblastoma (GBM), a setting of severe T cell exhaustion, revealed disproportionate loss of Tex_prog cells over time. Exhaustion concentrated within tumor-specific T cell subsets, with cognate antigen exposure requisite for acquisition of the Tex_term phenotype. Tumor-associated macrophages (TAMs)—not tumor cells—were the primary source of antigenic exposure governing the Tex_prog to Tex_term transition. TAM depletion increased frequencies of Tex_prog cells in multiple tumor models, increased PETER, and promoted responsiveness to αPD1 immunotherapy. Thus, targeting TAM-T cell interactions may further license checkpoint blockade responses.

DOI: 10.1016/j.immuni.2024.11.026

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00541-7

期刊信息

Immunity:《免疫》,创刊于1994年。隶属于细胞出版社,最新IF:43.474
官方网址:https://www.cell.com/immunity/home
投稿链接:https://www.editorialmanager.com/immunity/default.aspx