PKC agonism restricts innate immune suppression and promotes antigen cross-presentation in Triple Negative Breast Cancer

PKC 激动限制三阴性乳腺癌中的先天免疫抑制并促进抗原交叉呈递

• 批准号: 10387395
• 负责人: Mehdi Chaib
• 金额: $ 3.28万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387395
• 关键词: Address; Agonist; Antibodies; Antigen-Presenting Cells; Antigens; Antitumor Response; Automobile Driving; Award; Biological Assay; Bone Marrow; Breast Cancer Patient; CD8-Positive T-Lymphocytes; Cancer Biology; Cell Count; Cell Differentiation process; Cell physiology; Cells; Clinic; Cross Presentation; Cross-Priming; Cytotoxic T-Lymphocytes; Data; Databases; Dendritic Cells; Dependence; Equilibrium; FDA approved; Family; Frequencies; Generations; Goals; Immune; Immunity; Immunologist; Immunomodulators; Immunosuppression; Immunotherapy; In Vitro; Informatics; Investigation; Isoenzymes; Malignant Neoplasms; Minority; Modeling; Monoclonal Antibodies; Myelogenous; Myeloid Cell Activation; Myeloid Cells; Myeloid-derived suppressor cells; Natural Immunity; PEP005; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Phosphotransferases; Play; Population; Production; Protein Isoforms; Protein Kinase C; Research; Research Personnel; Resistance; Role; Science; Signal Transduction; Solid Neoplasm; Spleen; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic; Therapeutic Effect; Training; Tumor Antigens; Tumor Burden; Tumor Immunity; adaptive immunity; anti-PD-L1; anti-PD-L1 therapy; anti-tumor immune response; base; cancer therapy; conventional therapy; cytotoxic CD8 T cells; genetic signature; immune checkpoint blockade; immunogenic; improved; in vivo; innovation; loss of function; macrophage; malignant breast neoplasm; monocyte; mouse model; novel; orthotopic breast cancer; progenitor; prostratin; protein activation; protein expression; protein kinase C-delta; response; success; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor immunology; tumor microenvironment; tumor-immune system interactions

SUMMARY Immune checkpoint blockade (ICB) has revolutionized cancer therapy showing unprecedented long-term antitumor responses. However, most patients do not respond to ICB therapies due at least partly to immunosuppression. Immunotherapy non-responders have high levels of circulating myeloid-derived suppressor cells (MDSCs)- an immunosuppressive innate cell population that suppresses both innate and adaptive immunity. Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancers with poor responses to conventional therapies. TNBC patients harbor higher levels of MDSC populations compared to non-TNBC patients. Consequently, TNBC and other solid tumor patients who have high levels of circulating MDSCs respond poorly to ICB. Hence, strategies that reduce MDSC’s suppressive function while promoting cross-priming of CD8+ T cells are likely to be effectively combined with ICB for a maximum therapeutic benefit. Protein Kinase C (PKC) is a family of kinases composed of 11 isoforms that play a critical role in cell signaling. PKC delta (PKC) is the most abundant isoform in myeloid cells and plays an important role in dendritic cell (DC) function. To date, the role of PKC in myeloid cells in cancer is unknown. Using varied informatic approaches in patient databases, I found that BC patients with both high expression of PRKCD and either high expression of CD8+ T cell or low expression of MDSC gene signatures in tumors had a significantly greater overall survival compared to other groups, suggesting support for activation of PKC. Novel preliminary data suggests that PKC agonism using FDA-approved PEP005 and prostratin reduced MDSC generation from bone marrow progenitors specifically via activation of PKC isoform. PKC agonism induced MDSC differentiation to CD103+ DC-like cells both ex-vivo and in vivo. Additionally, PEP005-treated MDSCs lost their suppressive capacity on CD8+ T cells in both in vitro and in vivo pilot suppression assays and efficiently cross-primed OT-I CD8+ T cells. Mechanistic studies reveal transcription factor IRF5 as a potential target of PKC-to be explored in this proposal. Based on rigorously generated pilot data, I hypothesize that PKC agonism combined with agonistic CD40 mAb will sensitize TNBC tumors to ICB through induced differentiation of MDSCs to DC-like cells via activation of PKC and its downstream target IRF5. CD40 is mainly expressed by myeloid cells and its activation has been shown to effectively activate antigen-presenting cells. Aim 1 & 2 will determine if PKC activation controls MDSC and DC phenotype and function and will determine to what extent pharmacologic activation of PKC in combination with agonistic CD40 mAb improves anti-PD-L1 therapy in TNBC mouse models. The proposed training will prepare me for my long-term goal of becoming a tumor immunologist with a research objective to develop novel immunomodulatory therapeutic approaches against solid tumors as an independent investigator.

总结 免疫检查点阻断（ICB）彻底改变了癌症治疗，显示出前所未有的长期疗效。 抗肿瘤反应。然而，大多数患者对ICB治疗没有反应，至少部分原因是 免疫抑制免疫治疗无应答者的循环髓源性抑制因子水平较高 细胞（MDSC）-一种免疫抑制性先天细胞群，抑制先天和适应性 免疫力三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型，具有较差的免疫原性。 对传统疗法的反应。TNBC患者具有更高水平的MDSC群体， 非TNBC患者。因此，TNBC和其他具有高水平循环肿瘤的实体瘤患者， MDSC对ICB反应较差。因此，降低MDSC的抑制功能同时促进MDSC表达的策略是可行的。 CD 8 + T细胞的交叉致敏可能与ICB有效地组合以获得最大的治疗益处。 蛋白激酶C（PKC）是一个由11种亚型组成的激酶家族，在细胞信号传导中起关键作用。 蛋白激酶C δ（PKC δ）是髓系细胞中含量最丰富的一种亚型，在树突状细胞（DC）中起重要作用 功能迄今为止，PKC β在骨髓细胞中的作用在癌症中是未知的。使用各种信息方法， 患者数据库中，我发现BC患者既有PRKCD的高表达， 肿瘤中CD 8 + T细胞或MDSC基因标签的低表达具有显著更高的总生存率。 与其他组相比，提示支持PKC β的激活。新的初步数据表明，PKC 使用FDA批准的PEP 005和prostratin的激动作用减少了骨髓祖细胞的MDSC生成 特别是通过激活PKC β亚型。PKC激动诱导MDSC向CD 103 + DC样细胞分化 包括离体和体内。此外，PEP 005处理的MDSC丧失了对CD 8 + T细胞的抑制能力， 体外和体内试验性抑制测定和有效交叉致敏的OT-I CD 8 + T细胞。机械论 研究表明转录因子IRF 5是PKC β的潜在靶点-在本研究中有待探索。基于 严格生成的试验数据，我假设PKC激动剂与激动性CD 40 mAb联合使用， 通过活化PKC β 1诱导MDSC分化为DC样细胞，使TNBC肿瘤对ICB敏感 及其下游靶点IRF 5。CD 40主要由骨髓细胞表达并已显示其激活 以有效地激活抗原呈递细胞。目的1和2将确定PKC β 1激活是否控制MDSC， DC的表型和功能，并将决定在何种程度上的药理学激活PKC的组合 与激动性CD 40 mAb联合使用改善了TNBC小鼠模型中的抗PD-L1治疗。拟议的培训将 为我成为一名肿瘤免疫学家的长期目标做好准备， 作为独立研究者，研究针对实体瘤的免疫调节治疗方法。