中文摘要：

單核吞噬細(xì)胞（MPs）在維持組織穩(wěn)態(tài)中發(fā)揮關(guān)鍵作用，但同時(shí)也會(huì)促進(jìn)腫瘤進(jìn)展，并導(dǎo)致腫瘤對(duì)免疫檢查點(diǎn)阻斷療法（ICB）產(chǎn)生耐藥。靶向單核吞噬細(xì)胞有望成為提升免疫檢查點(diǎn)阻斷療效的有效策略。本研究證實(shí)，絲氨酸 / 蘇氨酸激酶蛋白激酶 Cδ（PKCδ） 在人和小鼠腫瘤內(nèi)的單核吞噬細(xì)胞中呈高表達(dá)。

與野生型小鼠相比，PKCδ 基因敲除（PKCδ?/?） 小鼠的腫瘤進(jìn)展受到抑制，且對(duì)抗 PD-1 療法的應(yīng)答提升。PKCδ?/?小鼠的腫瘤微環(huán)境呈現(xiàn)偏向 Th1 型的免疫應(yīng)答特征，抗原提呈能力與 T 細(xì)胞活化水平均有所增強(qiáng)。

在活體動(dòng)物中清除單核吞噬細(xì)胞后，野生型小鼠的腫瘤生長受到影響，而 PKCδ?/?小鼠則無明顯變化。將 PKCδ?/?的 M2 樣巨噬細(xì)胞與腫瘤細(xì)胞共同接種至野生型小鼠體內(nèi)，相較于野生型（PKCδ?/?）對(duì)照組，可顯著延緩腫瘤生長，并大幅增強(qiáng)腫瘤內(nèi)部的 T 細(xì)胞活化。

PKCδ 基因缺失可通過激活I(lǐng) 型與 II 型干擾素信號(hào)通路，實(shí)現(xiàn)單核吞噬細(xì)胞的表型重編程。綜上，靶向 PKCδ 能夠重塑單核吞噬細(xì)胞功能，進(jìn)而增強(qiáng)免疫檢查點(diǎn)阻斷療法的抗腫瘤效果。

英文摘要：

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.

論文信息：

論文題目：Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer

期刊名稱：Science Advances

時(shí)間期卷：Vol 7, Issue 51(2023)

在線時(shí)間：2023年12月22日

DOI: 10.1126/sciadv.add3231

產(chǎn)品信息：

貨號(hào)：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes&Control Liposomes

辦事處：靶點(diǎn)科技

Clodronate Liposomes氯膦酸鹽脂質(zhì)體在敲除小鼠腫瘤模型種清除巨噬細(xì)胞。荷蘭Liposoma巨噬細(xì)胞清除劑ClodronateLiposomes見刊于Science Advances：蛋白激酶 Cδ 調(diào)控單核吞噬細(xì)胞，并削弱腫瘤的免疫治療應(yīng)答。

Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體清除巨噬細(xì)胞的材料和方法：

Macrophage depletion

All reagents were obtained from Sigma-Aldrich (St. Louis, MO) unless otherwise noted. Fetal bovine serum (FBS; Gibco, Waltham, MA), 100× l-glutamine, 100× penicillin/streptomycin HyClone (Pittsburgh, PA), and Gibco 100× antibiotic mix were obtained from Thermo Fisher Scientific (Waltham, MA). RPMI 1640, Dulbecco’s modified Eagle’s medium (DMEM), and Matrigel are from Corning (Tewksbury, MA). Mouse recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin- 6 (IL-6), IL-4, macrophage CSF (M-CSF), and FMS-like tyrosine kinase 3 ligand (FLT3L) were obtained from BioLegend (San Diego, CA). OVA was obtained from Thermo Fisher Scientific. Mouse IFN-γ ELISA kit was obtained from R&D Systems (Minneapolis, MN). Mouse CD4+ T cell isolation kit and CD8+ T cell isolation kit were obtained from Miltenyi Biotec (Auburn, CA). Clodronate and control liposomes were obtained from Liposoma (Amsterdam, The Netherlands). In vivo anti-mouse CD40, anti-mouse PD-1, anti-mouse Ly6C monoclonal antibodies, and their controls (rat IgG2a) were all obtained from Bio X Cell (Lebanon, NH). KO-validated PKCδ antibody and phycoerythrin/Cy7 conjugation kit were obtained from Abcam (Cambridge, UK). Flow cytometry antibodies, compensation beads, and reagents are described in table S1 [Tonbo Biosciences Inc. (San Diego, CA), Thermo Fisher, and BioLegend].

巨噬細(xì)胞清除材料和方法文獻(xiàn)截圖：