Therapeutic targeting of CD206+ TAMs to enhance adaptive and innate anti-tumor immune responses in metastatic castration-resistant prostate cancer

CD206 TAM 的治疗靶向增强转移性去势抵抗性前列腺癌的适应性和先天抗肿瘤免疫反应

• 批准号: 10731906
• 负责人: Jelani Chinelo Zarif
• 金额: $ 45.75万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731906
• 关键词: CD8-Positive T-Lymphocytes; Cancer Model; Cancer Patient; Cells; Clinical Trials; Diagnosis; Disease; Disease Progression; Endocytosis; Exclusion; Goals; Growth; Host Defense; Human; Immune; Immune Evasion; Immune Targeting; Immune response; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Inflammatory; Invaded; Lysosomes; Macrophage; Malignant Bone Neoplasm; Malignant neoplasm of prostate; Measures; Mediating; Mediator; Medical; Metastasis Suppression; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Molecular Conformation; Mus; NK Cell Activation; Natural Killer Cells; Neoplasm Metastasis; Nivolumab; Pathway interactions; Patient-Focused Outcomes; Patients; Peptides; Phagocytosis; Phagocytosis Induction; Phagosomes; Phenotype; Play; Prostatic Neoplasms; Publishing; RNA Sequences; Refractory; Regulation; Research; Resistance; Role; Sampling; Surface; T-Lymphocyte; Therapeutic; Therapeutic Uses; Time; Tumor Immunity; Tumor Promotion; Tumor-associated macrophages; Xenograft Model; adaptive immune response; analog; angiogenesis; anti-PD-L1; anti-PD-L1 therapy; anti-PD1 therapy; anti-tumor immune response; cancer cell; castration resistant prostate cancer; cell growth; checkpoint therapy; cytotoxic; genetic signature; humanized mouse; immune cell infiltrate; immune resistance; in vivo; innovation; mannose receptor; men; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; patient response; programs; prostate cancer progression; receptor; recruit; response; synergism; therapeutic target; therapy resistant; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

Metastatic castration-resistant prostate cancer (mCRPC) tumors are characterized by an abundant, tumor- promoting immune infiltrate that is composed of immune suppressive tumor-associated macrophages (TAMs). These cells promote angiogenesis, suppress T cell recruitment and/or activation and promote metastasis in mCRPC. T cells exclusion by TAMs in mCRPC leads to resistance of immune checkpoint therapy. Annually, nearly 270,000 men will be diagnosed with prostate cancer (PCa) in the U.S. in 2021 and more than 33,000 men will die from this disease. Therefore, mCRPC is an unmet medical need and there is an urgent need to develop innovative therapeutics that would target immune suppressive TAMs that will enhance responses to therapies and benefit mCRPC patients. We sought to re-establish an anti-tumor immune response by targeting surface receptors on TAMs that help drive PCa progression. Using human PCa tumor microarrays, we published that the macrophage mannose receptor (CD206) increased during PCa progression to mCRPC. Our team then selectively targeted of CD206 using RP-182, a 10-mer amphipathic analog of host defense peptide that selectively induces a conformational switch of CD206 expressed on TAMs. RP-182-mediated induction of CD206 in human and murine TAMs elicits a program of endocytosis, phagosomelysosome formation, cancer cell phagocytosis, and reprograms immune-suppressive TAMs to an anti-tumor inflammatory phenotype. In syngeneic and autochthonous murine cancer models, RP-182 suppressed tumor growth, extended survival, and was an effective combination partner with chemo- or immune checkpoint therapy. In the proposed studies, we will evaluate the premise that CD206+ TAMs play an essential role in PCa tumor progression and therapeutic resistance. We hypothesize that the immune-suppressive CD206+ TAMs drive PCa resistance to immunotherapies and therapeutic inhibition of CD206+ TAMs will re-educate TAMs to the pro-inflammatory phenotype, enhance anti-tumor immune responses and will synergize with chemo- or immune checkpoint therapy. The specific aims of this proposal are: 1) Establish the contribution of CD206+ TAM function in PCa tumorigenesis and immune evasion; 2) Elucidate how inhibition of CD206+ TAMs may synergize wirh anti-PD- L1 to enhance anti-tumor immunity 3) Correlate CD206+ TAM infiltrate with Nivolumab response, PCa bone metastasis and patient outcomes. Utilizing a humanized mice and a novel syngeneic mCRPC mouse model in which tumors are heavily infiltrated with CD206+ TAMs and refractory to immune checkpoint therapy, we will characterize the changes in adaptive and immune responses after CD206 is inhibited both in vitro and in vivo. In the third aim, we will measure CD206+ TAM expression in human PCa from mCRPC bone and single-cell RNA sequenced PCa tumors from a Nivolumab clinical trial. Targeting CD206+ TAMs in syngeneic murine tumor models and patient-derived xenotransplantation models in humanized mice has great potential to alter the tumor microenvironment and enhance anti-tumor immune responses that may lead to novel therapeutics for mCRPC.

转移性cast割的前列腺癌（MCRPC）肿瘤的特征是丰富的肿瘤 促进由免疫抑制性肿瘤相关巨噬细胞（TAM）组成的免疫浸润。 这些细胞促进血管生成，抑制T细胞募集和/或激活，并促进转移 MCRPC。 TAM在MCRPC中排除的T细胞会导致免疫检查点疗法的抗性。每年 2021年，美国将有近27万名男性被诊断出患有前列腺癌（PCA）和33,000多名男性 会死于这种疾病。因此，MCRPC是未满足的医疗需求，迫切需要开发 创新的治疗剂将以免疫抑制性TAM为目标，以增强对疗法的反应 并使MCRPC患者受益。我们试图通过靶向表面重新建立抗肿瘤免疫反应 TAM上有助于推动PCA进展的受体。使用人类PCA肿瘤微阵列，我们发表了 在PCA进展为MCRPC期间，巨噬细胞甘露糖受体（CD206）增加。然后我们的团队 使用RP-182选择性地针对CD206，这是一种10-Mer的两亲性类似物的宿主防御肽类似物 有选择地诱导在TAM上表达的CD206的构象开关。 RP-182介导的CD206诱导 在人和鼠类中，tams引发了一个内吞作用，吞噬体形成，癌细胞的程序 吞噬作用，并将免疫抑制性TAM重新编程为抗肿瘤炎症表型。在 合成和自毒鼠类癌模型，RP-182抑制了肿瘤的生长，延长的生存和 是化学或免疫检查点疗法的有效组合伙伴。在拟议的研究中，我们 将评估CD206+ TAMS在PCA肿瘤进展和治疗中起重要作用的前提 反抗。我们假设免疫抑制CD206+ TAMS驱动PCA耐药性 CD206+ TAM的免疫疗法和治疗性抑制作用将重新教育TAMS促炎症 表型，增强抗肿瘤免疫反应，并将与化学或免疫检查点协同作用 治疗。该提案的具体目的是：1）确定CD206+ TAM功能在PCA中的贡献 肿瘤发生和免疫逃避； 2）阐明CD206+ TAM的抑制如何协同wirh抗PD- L1增强抗肿瘤免疫力3）将CD206+ TAM浸润与Nivolumab响应，PCA骨骼相关 转移和患者结局。利用人源化的小鼠和新型的同性MCRPC小鼠模型 哪些肿瘤被CD206+ TAM大量浸润，并难治于免疫检查点疗法，我们将 表征CD206后适应性和免疫反应的变化在体外和体内都受到抑制。 在第三个目标中，我们将测量MCRPC骨和单细胞的人PCA中CD206+ TAM表达 RNA从Nivolumab临床试验中测序PCA肿瘤。靶向同性鼠肿瘤中的CD206+ TAM 人源化小鼠中的模型和患者衍生的异种移植模型具有改变肿瘤的巨大潜力 微环境并增强了可能导致MCRPC新型治疗剂的抗肿瘤免疫反应。