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Yu, Jiali; Green, Michael D; Li, Shasha; Sun, Yilun; Journey, Sara N; Choi, Jae Eun; Rizvi, Syed Monem; Qin, Angel; Waninger, Jessica J; Lang, Xueting; Chopra, Zoey; El Naqa, Issam; Zhou, Jiajia; Bian, Yingjie; Jiang, Long; Tezel, Alangoya; Skvarce, Jeremy; Achar, Rohan K; Sitto, Merna; Rosen, Benjamin S; Su, Fengyun; Narayanan, Sathiya P; Cao, Xuhong; Wei, Shuang; Szeliga, Wojciech; Vatan, Linda; Mayo, Charles; Morgan, Meredith A; Schonewolf, Caitlin A; Cuneo, Kyle; Kryczek, Ilona; Ma, Vincent T; Lao, Christopher D; Lawrence, Theodore S; Ramnath, Nithya; Wen, Fei; Chinnaiyan, Arul M; Cieslik, Marcin; Alva, Ajjai; Zou, Weiping
Nature medicine, 01/2021, Letnik: 27, Številka: 1Journal Article
Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8 T cells from systemic circulation. Within the liver, activated antigen-specific Fas CD8 T cells undergo apoptosis following their interaction with FasL CD11b F4/80 monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8 T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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