Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer.
Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer.
复制标题
蛋白激酶C δ调节单核吞噬细胞并阻碍癌症免疫治疗的反应。
DOI：
10.1126/sciadv.add3231
复制
发表时间：
2023-12-22
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
单核巨噬细胞(MPS)在组织内稳态中起着至关重要的作用；然而，MPS也有助于肿瘤的进展和对免疫检查点阻断(ICB)的抵抗。靶向MPS可能是提高ICB疗效的有效策略。我们报道了蛋白激酶C增量(PKCδ)是一种丝氨酸/苏氨酸激酶，在人和小鼠肿瘤中由MPS大量表达。与野生型相比，pkcδ−/−小鼠的肿瘤进展速度较慢，对抗PD-1抗体的反应增强。来自pkcδ−/−小鼠的肿瘤表现出th1偏斜的免疫反应，包括抗原呈递增加和T细胞激活。体内MPS的耗尽改变了对照组小鼠的肿瘤生长，但不改变PKCδ−/−小鼠的肿瘤生长。与pKCδ−/−+/+对照相比，pKCδM2样巨噬细胞与肿瘤细胞共注射入野生型小鼠可显著延缓肿瘤生长，并显著增加瘤内T细胞的活化。PKCδ缺陷通过激活I型和II型干扰素信号使MPS重新编程。因此，PKCδ可能被靶向重新编程MPS以增强ICB的疗效。PKCδ是一种先天免疫检查点，可促进癌症的免疫抑制。
Mononuclear phagocytes (MPs) play a crucial role in tissue homeostasis; however, MPs also contribute to tumor progression and resistance to immune checkpoint blockade (ICB). Targeting MPs could be an effective strategy to enhance ICB efficacy. We report that protein kinase C delta (PKCδ), a serine/threonine kinase, is abundantly expressed by MPs in human and mouse tumors. PKCδ−/− mice displayed reduced tumor progression compared to wild types, with increased response to anti–PD-1. Tumors from PKCδ−/− mice demonstrated TH1-skewed immune response including increased antigen presentation and T cell activation. Depletion of MPs in vivo altered tumor growth in control but not PKCδ−/− mice. Coinjection of PKCδ−/− M2-like macrophages with cancer cells into wild-type mice markedly delayed tumor growth and significantly increased intratumoral T cell activation compared to PKCδ+/+ controls. PKCδ deficiency reprogrammed MPs by activating type I and type II interferon signaling. Thus, PKCδ might be targeted to reprogram MPs to augment ICB efficacy. PKCδ is an innate immune checkpoint that promotes immune suppression in cancer.
登录
查看更多内容
影响因子：
14.9
作者：
Gene Ontology Consortium
通讯作者：
Gene Ontology Consortium
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
16.6
作者：
Alicea-Torres K;Sanseviero E;Gui J;Chen J;Veglia F;Yu Q;Donthireddy L;Kossenkov A;Lin C;Fu S;Mulligan C;Nam B;Masters G;Denstman F;Bennett J;Hockstein N;Rynda-Apple A;Nefedova Y;Fuchs SY;Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
64.5
作者：
Binnewies, Mikhail;Mujal, Adriana M.;Krummel, Matthew F.
通讯作者：
Krummel, Matthew F.
影响因子：
8
作者：
D'Costa, AM;Robinson, JK;Denning, MF
通讯作者：
Denning, MF