Targeting CD5 on Tumor-associated T and B cells to improve PD-1 blockade in Breast Cancer

将 CD5 靶向肿瘤相关 T 细胞和 B 细胞以改善乳腺癌中的 PD-1 阻断

• 批准号: 10044774
• 负责人: CHUNYAN ZHANG
• 金额: $ 45.25万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044774
• 关键词: Antibodies; Antibody Therapy; B-Cell Neoplasm; B-Lymphocytes; Biological Assay; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; CD8-Positive T-Lymphocytes; CD8B1 gene; Carnitine Palmitoyltransferase I; Cells; Clinical; Data; Effector Cell; Enzymes; Fc Receptor; Gene Expression; Gene Expression Profile; Glycolysis; IL6 gene; Immune; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Interferon Type II; Interleukin 6 Receptor; Interleukin-10; Malignant Neoplasms; Metabolic; Metabolism; Mus; PFKM gene; Pathway interactions; Production; Role; STAT3 gene; Signal Transduction; T-Lymphocyte; Testing; Tumor Immunity; Up-Regulation; anti-tumor immune response; checkpoint inhibition; clinical effect; cytotoxicity; exhaustion; fatty acid oxidation; genetic signature; improved; in vitro activity; in vivo; inhibitor/antagonist; insight; malignant breast neoplasm; mouse model; nano-string; neoplastic cell; novel; novel strategies; novel therapeutics; outcome forecast; programmed cell death ligand 1; programmed cell death protein 1; protein expression; receptor; receptor binding; response; transcription factor; treatment response; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

PROJECT SUMMARY / ABSTRACT Triple negative breast cancer (TNBC) is a highly aggressive type of breast cancer that has a poor prognosis and limited treatment. Immune checkpoint inhibition, such as programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1), represents a major recent breakthrough in the treatment of diverse cancer including TNBC. Blocking PD-1 and PD-L1 interaction by antibodies has shown promising clinical effects. However, the response rate to PD-1 or PD-L1 antibody remains only at about 4.8%-26% in TNBC patients. A daunting challenge for improving efficacy of immunotherapy such as PD-1 antibody therapy is how to turn suppression CD8+ T cells to infiltrate tumor and kill tumor cells after the checkpoint- imposed brake is removed. Our extensive preliminary studies suggest that persistent STAT3 activation is critical for suppression of both innate and adaptive antitumor immunity. Ablating the Stat3 gene in T cells drastically induces CD8 TEFF cell tumor infiltration and antitumor effector functions, which mainly is through up-regulation of IFNγ and its inducible factors. However, the mechanism by which STAT3, a transcription factor, inhibits IFNγ remains unclear until we recently identified that STAT3 directly upregulates Carnitine palmitoyltransferase 1b (CPT1b) to promote fatty acid oxidation (FAO), which inhibits glycolysis and IFNγ expression in tumor CD8 T cells. However, to date clinically available STAT3 inhibitors are mainly JAK inhibitors, and JAKs are required for IFNγ triggered activation signaling, thus resulting in broader inhibition of targets that may be required for effector cell antitumor activities. In contrast, CD5 and PD-1 antibodies are receptor/pathway-limited and not expected to block JAK activation by other immunostimulatory molecules. Preliminary data indicate that CD5 and PD-1 are co- expressed on mouse breast cancer T and B cells, and both CD5 and PD-1 activate STAT3 and inhibit IFNγ which is necessary for therapeutic responses to PD-1/PD-L1 axis blockade. These extensive data led us to hypothesize that targeting CD5 in tumor-promoting CD5+ B cells and T cells enables PD-1 antibody therapy to effectively turn STAT3 dominance/IFNγ deficiency into IFNγ-rich anti-tumor immune activity in breast cancer mouse model. The central hypothesis will be tested in two aims: Aim 1. To assess the role of CD5/PD-1-STAT3 in regulating FAO/glycolysis metabolism and suppressing the CD8+ T cells capacity for anti-tumor function. Aim 2. To assess whether targeting CD5 on CD5+ B and T cells alters metabolism to enhance the anti-breast cancer effects of PD-1 blockade in mouse breast cancer model.

项目概要/摘要 三阴性乳腺癌（TNBC）是一种高度侵袭性的乳腺癌， 预后不良，治疗有限。免疫检查点抑制，例如程序化的 死亡配体 1 (PD-L1) 和受体程序性细胞死亡蛋白 1 (PD-1)，代表 最近在治疗包括 TNBC 在内的多种癌症方面取得了重大突破。阻断 PD-1 抗体与PD-L1的相互作用已显示出有希望的临床效果。然而， TNBC 患者对 PD-1 或​​ PD-L1 抗体的缓解率仅维持在 4.8%-26% 左右。一个 提高PD-1抗体疗法等免疫疗法疗效的艰巨挑战是 如何在检查点后让抑制性CD8+ T细胞浸润肿瘤并杀死肿瘤细胞- 施加的制动被移除。我们广泛的初步研究表明，持续的 STAT3 激活对于抑制先天性和适应性抗肿瘤免疫至关重要。烧蚀 T细胞中的Stat3基因显着诱导CD8 TEFF细胞肿瘤浸润和抗肿瘤 效应功能，主要是通过上调IFNγ及其诱导因子实现的。 然而，转录因子STAT3抑制IFNγ的机制仍不清楚 直到我们最近发现 STAT3 直接上调肉碱棕榈酰转移酶 1b (CPT1b) 促进脂肪酸氧化 (FAO)，从而抑制糖酵解和 IFNγ 表达 肿瘤 CD8 T 细胞。然而，目前临床上可用的STAT3抑制剂主要是JAK 抑制剂和 JAK 是 IFNγ 触发激活信号传导所必需的，从而导致 更广泛地抑制效应细胞抗肿瘤活性可能所需的靶标。相比之下， CD5 和 PD-1 抗体受受体/通路限制，预计不会阻断 JAK 激活 通过其他免疫刺激分子。初步数据表明 CD5 和 PD-1 共同作用 在小鼠乳腺癌 T 细胞和 B 细胞上表达，CD5 和 PD-1 均激活 STAT3 并 抑制 IFNγ，这是对 PD-1/PD-L1 轴阻断的治疗反应所必需的。这些 大量数据使我们推测，靶向促进肿瘤的 CD5+ B 细胞和 T 细胞中的 CD5 细胞使 PD-1 抗体疗法能够有效地将 STAT3 优势/IFNγ 缺陷转化为 乳腺癌小鼠模型中富含 IFNγ 的抗肿瘤免疫活性。中心假设将 测试的两个目标： 目标 1. 评估 CD5/PD-1-STAT3 在调节中的作用 FAO/糖酵解代谢和抑制CD8+ T细胞抗肿瘤能力 功能。目标 2. 评估 CD5+ B 和 T 细胞上的 CD5 靶向是否会改变 代谢增强PD-1阻断小鼠乳腺的抗乳腺癌作用 癌症模型。