背景:雄激素剥夺疗法(ADT)是前列腺癌的一线治疗方法。在一些男人中,它们的肿瘤可能变得难治,导致去势抵抗前列腺癌(CRPC)的发展。这会导致肿瘤再生和转移,尽管正在进行治疗,并对患者生存产生负面影响。已知ADT刺激免疫抑制细胞如肿瘤相关巨噬细胞(TAMs)的积累,前列腺肿瘤中的骨髓来源的抑制细胞和调节性T细胞,以及功能低下的T细胞。在其他形式的癌症中,在化疗和放疗期间,原发肿瘤TAM已被证明在肿瘤血管周围积聚,他们驱使肿瘤复发。我们的目的是观察这种血管周(PV)TAM是否也在CRPC之前在ADT治疗的前列腺肿瘤中积累,and,如果是,是否选择性地诱导它们表达有效的免疫刺激剂,干扰素β(IFNβ),会刺激抗肿瘤免疫和延迟CRPC。
方法:我们使用多重免疫荧光来评估ADT对TAM分布和激活状态的影响,CD8+T细胞,小鼠和/或人前列腺肿瘤中的CD4+T细胞和NK细胞。然后我们用抗体包被,脂质纳米颗粒(LNP)选择性靶向STING激动剂,2\'3\'-cGAMP(cGAMP),ADT期间小鼠前列腺肿瘤中的PVTAMs。
结果:响应ADT而在血管周围高密度积累的TAM,并表达包括叶酸受体-β(FR-β)在内的肿瘤前表型标记,MRC1(CD206),CD169和VISTA。此外,在这些PV肿瘤区域中存在较高数量的非活性(PD-1-)CD8+T细胞和减少数量的活性(CD69+)NK细胞.在ADT治疗的肿瘤中,用FR-β抗体包被的LNP选择性地将cGAMP递送至PVTAMs,它们激活STING并上调IFNβ的表达。这导致PV肿瘤区域中活性CD8T细胞(以及CD4T细胞和NK细胞)的密度显着增加,并显著延迟CRPC的发作。在LNP施用期间CD8+T细胞的抗体消耗证明了这些细胞在由LNP诱导的CRPC延迟中的重要作用。
结论:一起,我们的数据表明,将STING激动剂靶向PVTAMs可用于延长前列腺癌ADT的治疗窗.
BACKGROUND: Androgen deprivation therapy (ADT) is a front-line treatment for prostate cancer. In some men, their tumors can become refractory leading to the development of castration-resistant prostate cancer (CRPC). This causes tumors to regrow and metastasize, despite ongoing treatment, and impacts negatively on patient survival. ADT is known to stimulate the accumulation of immunosuppressive cells like protumoral tumor-associated macrophages (TAMs), myeloid-derived suppressor cells and regulatory T cells in prostate tumors, as well as hypofunctional T cells. Protumoral TAMs have been shown to accumulate around tumor blood vessels during chemotherapy and radiotherapy in other forms of cancer, where they drive tumor relapse. Our aim was to see whether such perivascular (PV) TAMs also accumulate in ADT-treated prostate tumors prior to CRPC, and, if so, whether selectively inducing them to express a potent immunostimulant, interferon beta (IFNβ), would stimulate antitumor immunity and delay CRPC.
METHODS: We used multiplex immunofluorescence to assess the effects of ADT on the distribution and activation status of TAMs, CD8+T cells, CD4+T cells and NK cells in mouse and/or human prostate tumors. We then used antibody-coated, lipid nanoparticles (LNPs) to selectively target a STING agonist, 2\'3\'-cGAMP (cGAMP), to PV TAMs in mouse prostate tumors during ADT.
RESULTS: TAMs accumulated at high density around blood vessels in response to ADT and expressed markers of a protumoral phenotype including folate receptor-beta (FR-β), MRC1 (CD206), CD169 and VISTA. Additionally, higher numbers of inactive (PD-1-) CD8+T cells and reduced numbers of active (CD69+) NK cells were present in these PV tumor areas. LNPs coated with an antibody to FR-β selectively delivered cGAMP to PV TAMs in ADT-treated tumors, where they activated STING and upregulated the expression of IFNβ. This resulted in a marked increase in the density of active CD8+T cells (along with CD4+T cells and NK cells) in PV tumor areas, and significantly delayed the onset of CRPC. Antibody depletion of CD8+T cells during LNP administration demonstrated the essential role of these cells in delay in CRPC induced by LNPs.
CONCLUSIONS: Together, our data indicate that targeting a STING agonist to PV TAMs could be used to extend the treatment window for ADT in prostate cancer.