CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Targeting the immune microenvironment for ovarian cancer therapy.
Targeting the immune microenvironment for ovarian cancer therapy.
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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性肿瘤微环境（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，已成为癌症治疗的突破性进展。
然而，在OC中，这些抑制剂未能证明患者结局有显著改善，且现有生物标志物尚未识别出有前景的亚组。因此，仍然迫切需要理解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策略。本综述旨在概述OC TME，并探索其作为治疗策略的潜力。TIL（肿瘤浸润淋巴细胞）（TILs）是OC TME中的主要参与者。关于针对OC抗原的自发性TILS反应的证据不断积累。活化的T辅助细胞分泌多种炎症细胞因子，对细胞毒性T细胞具有支持作用。
同时，成熟B细胞被招募，并通过靶抗原的调理作用和T细胞招募发挥显著的抗肿瘤作用。巨噬细胞也构成先天免疫的重要亚群（M1巨噬细胞），同时参与免疫刺激环境。
最后，OC已显示能引发显著的NK 细胞免疫反应，在无需预先致敏的情况下发挥直接细胞毒性。尽管存在这种初始细胞毒性，OC细胞仍发展出多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，并有效逃避免疫反应。
因此，OC TME主要被免疫抑制细胞浸润，如FOXP3+调节性T细胞、M2极化巨噬细胞和髓源性抑制细胞。尽管存在这种强烈的免疫抑制状态，PD-1/PD-L1抑制剂仍未能改善预后。除PD-1/PD-L1外，OC还表达多种其他有助于免疫逃逸的免疫检查点，每一个都代表潜在的免疫靶点。新型免疫疗法正试图克服免疫抑制状态，并利用抗体、过继细胞疗法或疫苗诱导特异性免疫反应。
总体而言，OC TME既带来机遇也带来障碍。免疫治疗方法持续显示出前景，下一代抑制剂提供了令人兴奋的机会。然而，根据个体免疫特征定制疗法对于这些治疗的成功至关重要。
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.
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