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衰老通过诱导免疫抑制性肿瘤微环境来导致免疫疗法耐药性。

Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment.

机构信息

Centre de recherche du CHU Sainte-Justine, Montréal, QC, Canada.

Département de pharmacologie et physiologie (Université de Montréal, Montréal, QC, Canada.

出版信息

Nat Commun. 2024 Mar 18;15(1):2435. doi: 10.1038/s41467-024-46769-9.

Abstract

The potential of immune checkpoint inhibitors (ICI) may be limited in situations where immune cell fitness is impaired. Here, we show that the efficacy of cancer immunotherapies is compromised by the accumulation of senescent cells in mice and in the context of therapy-induced senescence (TIS). Resistance to immunotherapy is associated with a decrease in the accumulation and activation of CD8 T cells within tumors. Elimination of senescent cells restores immune homeostasis within the tumor micro-environment (TME) and increases mice survival in response to immunotherapy. Using single-cell transcriptomic analysis, we observe that the injection of ABT263 (Navitoclax) reverses the exacerbated immunosuppressive profile of myeloid cells in the TME. Elimination of these myeloid cells also restores CD8 T cell proliferation in vitro and abrogates immunotherapy resistance in vivo. Overall, our study suggests that the use of senolytic drugs before ICI may constitute a pharmacological approach to improve the effectiveness of cancer immunotherapies.

摘要

免疫检查点抑制剂(ICI)的潜力可能在免疫细胞功能受损的情况下受到限制。在这里,我们表明,在小鼠和治疗诱导的衰老(TIS)的情况下,衰老细胞的积累会损害癌症免疫疗法的疗效。对免疫疗法的耐药性与肿瘤内 CD8 T 细胞的积累和激活减少有关。消除衰老细胞可恢复肿瘤微环境(TME)内的免疫平衡,并增加小鼠对免疫疗法的反应的存活率。使用单细胞转录组分析,我们观察到注射 ABT263(Navitoclax)可逆转 TME 中髓样细胞过度免疫抑制的特征。消除这些髓样细胞也可恢复体外 CD8 T 细胞的增殖,并在体内消除免疫疗法的耐药性。总的来说,我们的研究表明,ICI 前使用衰老细胞清除药物可能构成一种改善癌症免疫疗法效果的药理学方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1865/10948808/26ac47a7605a/41467_2024_46769_Fig1_HTML.jpg

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