针对卵巢癌治疗的免疫微环境。
Targeting the immune microenvironment for ovarian cancer therapy.
机构信息
Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), National University Hospital, Singapore, Singapore.
Yong Loo Lin School of Medicine and Cancer Science Institute (CSI), National University of Singapore (NUS), Singapore, Singapore.
出版信息
Front Immunol. 2023 Dec 18;14:1328651. doi: 10.3389/fimmu.2023.1328651. eCollection 2023.
Ovarian cancer (OC) is an aggressive malignancy characterized by a complex immunosuppressive tumor microenvironment (TME). Immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy by reactivating the antitumor immune response suppressed by tumor cells. However, in the case of OC, these inhibitors have failed to demonstrate significant improvements in patient outcomes, and existing biomarkers have not yet identified promising subgroups. Consequently, there remains a pressing need to understand the interplay between OC tumor cells and their surrounding microenvironment to develop effective immunotherapeutic approaches. This review aims to provide an overview of the OC TME and explore its potential as a therapeutic strategy. Tumor-infiltrating lymphocytes (TILs) are major actors in OC TME. Evidence has been accumulating regarding the spontaneous TILS response against OC antigens. Activated T-helpers secrete a wide range of inflammatory cytokines with a supportive action on cytotoxic T-cells. Simultaneously, mature B-cells are recruited and play a significant antitumor role through opsonization of target antigens and T-cell recruitment. Macrophages also form an important subset of innate immunity (M1-macrophages) while participating in the immune-stimulation context. Finally, OC has shown to engage a significant natural-killer-cells immune response, exerting direct cytotoxicity without prior sensitization. Despite this initial cytotoxicity, OC cells develop various strategies to induce an immune-tolerant state. To this end, multiple immunosuppressive molecules are secreted to impair cytotoxic cells, recruit regulatory cells, alter antigen presentation, and effectively evade immune response. Consequently, OC TME is predominantly infiltrated by immunosuppressive cells such as FOXP3 regulatory T-cells, M2-polarized macrophages and myeloid-derived suppressor cells. Despite this strong immunosuppressive state, PD-1/PD-L1 inhibitors have failed to improve outcomes. Beyond PD-1/PD-L1, OC expresses multiple other immune checkpoints that contribute to immune evasion, and each representing potential immune targets. Novel immunotherapies are attempting to overcome the immunosuppressive state and induce specific immune responses using antibodies adoptive cell therapy or vaccines. Overall, the OC TME presents both opportunities and obstacles. Immunotherapeutic approaches continue to show promise, and next-generation inhibitors offer exciting opportunities. However, tailoring therapies to individual immune characteristics will be critical for the success of these treatments.
卵巢癌(OC)是一种侵袭性恶性肿瘤,其特征是复杂的免疫抑制肿瘤微环境(TME)。免疫检查点抑制剂通过重新激活被肿瘤细胞抑制的抗肿瘤免疫反应,成为癌症治疗的突破。然而,在 OC 的情况下,这些抑制剂未能显著改善患者的预后,并且现有的生物标志物尚未确定有前途的亚组。因此,仍然迫切需要了解 OC 肿瘤细胞与其周围微环境之间的相互作用,以开发有效的免疫治疗方法。本综述旨在概述 OC 的 TME,并探讨其作为治疗策略的潜力。肿瘤浸润淋巴细胞(TILs)是 OC TME 的主要参与者。关于针对 OC 抗原的自发 TILS 反应的证据不断积累。激活的 T 辅助细胞分泌广泛的炎症细胞因子,对细胞毒性 T 细胞具有支持作用。同时,成熟的 B 细胞被募集并通过靶向抗原的调理和 T 细胞募集发挥重要的抗肿瘤作用。巨噬细胞也形成固有免疫的重要亚群(M1 巨噬细胞),同时参与免疫刺激环境。最后,OC 已显示出可引起大量自然杀伤细胞免疫反应,无需预先致敏即可发挥直接细胞毒性作用。尽管有这种初始细胞毒性,OC 细胞仍会产生各种策略来诱导免疫耐受状态。为此,多种免疫抑制分子被分泌以损害细胞毒性细胞,招募调节性细胞,改变抗原呈递,并有效地逃避免疫反应。因此,OC TME 主要浸润有免疫抑制细胞,如 FOXP3 调节性 T 细胞、M2 极化的巨噬细胞和髓系来源的抑制细胞。尽管存在这种强烈的免疫抑制状态,但 PD-1/PD-L1 抑制剂并未改善预后。除了 PD-1/PD-L1,OC 还表达多种其他免疫检查点,有助于免疫逃逸,每个免疫检查点都代表潜在的免疫治疗靶点。新型免疫疗法试图通过使用抗体过继细胞疗法或疫苗来克服免疫抑制状态并诱导特异性免疫反应。总的来说,OC TME 既有机会也有挑战。免疫治疗方法继续显示出前景,下一代抑制剂带来了令人兴奋的机会。然而,将治疗方法定制为个体免疫特征对于这些治疗的成功将是至关重要的。