The Pellino1–PKCθ Signaling Axis Is an Essential Target for Improving Antitumor CD8+ T-lymphocyte Function
| Autor: | Jihyun Park, Si-Yeon Lee, Yoon Jeon, Kyung-Mo Kim, Jin-Kwan Lee, Jiwon Ko, Eun-Ji Park, Joon-Sup Yoon, Baeki E. Kang, Dongryeol Ryu, Ho Lee, Su-Jin Shin, Heounjeong Go, Chang-Woo Lee |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Cancer Immunology Research. 10:327-342 |
| ISSN: | 2326-6074 2326-6066 |
| DOI: | 10.1158/2326-6066.cir-21-0419 |
| Popis: | CD8+ T cells play an important role in the elimination of tumors. However, the underlying mechanisms involved in eliciting and maintaining effector responses in CD8+ T cells remain to be elucidated. Pellino1 (Peli1) is a receptor signal-responsive ubiquitin E3 ligase, which acts as a critical mediator for innate immunity. Here, we found that the risk of developing tumors was dependent on Peli1 expression. Peli1 was upregulated in CD8+ T cells among tumor-infiltrating lymphocytes (TIL). In contrast, a deficit of Peli1 enhanced the maintenance and effector function of CD8+ TILs. The development of Peli1-deficient CD8+ TILs prevented T-cell exhaustion and retained the hyperactivated states of T cells to eliminate tumors. We also found that Peli1 directly interacted with protein kinase C-theta (PKCθ), a central kinase in T-cell receptor downstream signal transduction, but whose role in tumor immunology remains unknown. Peli1 inhibited the PKCθ pathway by lysine 48–mediated ubiquitination degradation in CD8+ TILs. In summary, the Peli1–PKCθ signaling axis is a common inhibitory mechanism that prevents antitumor CD8+ T-cell function, and thus targeting Peli1 may be a useful therapeutic strategy for improving cytotoxic T-cell activity. |
| Databáze: | OpenAIRE |
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