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

转移性去势抵抗性前列腺癌（mCRPC）肿瘤的特征是大量的肿瘤- 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/或活化，并促进肿瘤转移。 mCRPC。mCRPC中TAM对T细胞的排斥导致免疫检查点治疗耐药。每年， 到2021年，美国将有近270，000名男性被诊断患有前列腺癌（PCa）， 会死于这种疾病。因此，mCRPC是一种未满足的医疗需求，迫切需要开发 靶向免疫抑制性TAM的创新疗法， 使mCRPC患者受益。我们试图通过靶向肿瘤细胞表面， TAMs上的受体有助于推动PCa进展。使用人类PCa肿瘤微阵列，我们发表了， 巨噬细胞甘露糖受体（CD 206）在PCa进展为mCRPC期间增加。我们的团队 使用RP-182选择性靶向CD 206，RP-182是宿主防御肽的10聚体两亲性类似物， 选择性诱导TAM上表达的CD 206的构象转换。RP-182介导的CD 206诱导 在人和鼠TAM中，启动了内吞作用、吞噬体/溶酶体形成、癌细胞 吞噬作用，并将免疫抑制性TAM重编程为抗肿瘤炎性表型。在 在同基因和自体小鼠癌症模型中，RP-182抑制肿瘤生长，延长生存期， 是化疗或免疫检查点治疗的有效组合伙伴。在研究中，我们 将评估CD 206 + TAM在PCa肿瘤进展和治疗中发挥重要作用的前提。 阻力我们假设免疫抑制性CD 206 + TAM驱动PCa抵抗， CD 206 + TAM的免疫疗法和治疗性抑制将使TAM再教育为促炎性细胞因子。 表型，增强抗肿瘤免疫应答，并将与化疗或免疫检查点协同作用 疗法本研究的具体目的是：1）确定CD 206 + TAM功能在PCa中的作用 2）阐明了抑制CD 206 + TAM如何协同CD 206+抗PD-1抗体; 3）将CD 206 + TAM浸润与纳武单抗反应、PCa骨相关 转移和患者结果。利用人源化小鼠和新的同基因mCRPC小鼠模型， 对于CD 206 + TAM严重浸润且免疫检查点治疗难治的肿瘤，我们将 表征在体外和体内抑制CD 206后适应性和免疫应答的变化。 在第三个目标中，我们将测量来自mCRPC骨和单细胞的人PCa中的CD 206 + TAM表达。 RNA测序来自Nivolumab临床试验的PCa肿瘤。靶向同源鼠肿瘤中的CD 206 + TAM 在人源化小鼠中的肿瘤模型和患者来源的异种移植模型具有改变肿瘤的巨大潜力， 微环境和增强抗肿瘤免疫反应，可能导致新的治疗mCRPC。

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.