肿瘤细胞治疗研究
英文原题：IL-15 trans-presentation at the innate-adaptive interface: mechanisms and translation in cancer immunotherapy.
持久的抗肿瘤免疫需要固有免疫激活、抗原呈递、淋巴细胞致敏、迁移和效应功能。
持久的抗肿瘤免疫需要固有免疫激活、抗原呈递、淋巴细胞致敏、运输和效应功能。在免疫冷肿瘤中，树突状细胞和自然杀伤（NK）细胞激活不足限制了从肿瘤抗原识别向CD8 T细胞免疫的转变。白细胞介素-15（IL-15）是共同γ链细胞因子家族成员，在这一固有-适应性免疫界面上具有独特的受体递送系统。在天然反式呈递中，IL-15由抗原呈递细胞上的IL-15受体α（IL-15Rα）稳定，并呈递给相邻NK细胞或记忆CD8 T细胞上的CD122/CD132。这种接触依赖性排列支持NK细胞稳态、记忆CD8 T细胞维持和空间受限信号传导，同时避免IL-2依赖CD25的调节性T细胞偏好。IL-12、IL-15和IL-18可生成具有增强回忆反应的细胞因子诱导记忆样NK细胞。这些程序受到内在CISH反馈以及肿瘤相关TGF-β、PD-L1、TIGIT、腺苷和其他抑制通路的限制。药理学IL-15受体激动剂如N-803再现了反式呈递的某些受体结合特征，但未再现其天然来源细胞、接触或空间限制。膀胱内N-803联合卡介苗在BCG无应答非肌层浸润性膀胱癌中的持久活性确立了其局部联合治疗背景下的临床相关性，而全身性实体瘤研究显示药效学淋巴细胞扩增，但临床活性较为有限或多变。本叙述性综述综合了IL-15受体生物学、固有和适应性效应程序、反向调节及临床转化。它提出“先天免疫启动”作为一种机制性假说：适时介入IL-15轴可能增强受损的先天免疫向适应性免疫的交接，其疗效取决于给药途径、组织背景、联合治疗、暴露方案和患者选择。
Durable antitumor immunity requires innate activation, antigen presentation, lymphocyte priming, trafficking, and effector function. In immunologically cold tumors, deficient dendritic-cell and natural killer (NK)-cell activation limits the transition from tumor-antigen recognition to CD8 T-cell immunity. Interleukin-15 (IL-15) is a member of the common gamma-chain cytokine family with a distinctive receptor-delivery system at this innate-adaptive interface. In native trans-presentation, IL-15 is stabilized by IL-15 receptor alpha (IL-15Rα) on an antigen-presenting cell and presented to CD122/CD132 on an apposed NK or memory CD8 T cell. This contact-dependent arrangement supports NK-cell homeostasis, memory CD8 T-cell maintenance, and spatially restricted signaling while avoiding the CD25-dependent regulatory T-cell preference of IL-2. IL-12, IL-15, and IL-18 can generate cytokine-induced memory-like NK cells with enhanced recall. These programs are constrained by intrinsic CISH feedback and by tumor-associated TGF- β , PD-L1, TIGIT, adenosine, and other suppressive pathways. Pharmacologic IL-15 receptor agonizts such as N-803 reproduce selected receptor-binding features of trans-presentation but do not reproduce its native source-cell, contact, or spatial restrictions. The durable activity of intravesical N-803 plus bacillus Calmette-Guérin in BCG-unresponsive non-muscle-invasive bladder cancer establishes clinical relevance in a localized combination setting, whereas systemic solid-tumor studies have shown pharmacodynamic lymphocyte expansion with more limited or variable clinical activity. This narrative review synthesizes IL-15 receptor biology, innate and adaptive effector programs, counter-regulation, and clinical translation. It presents the 'innate bootstrap' as a mechanistic hypothesis: appropriately timed IL-15-axis engagement may strengthen an impaired innate-to-adaptive handoff, with efficacy determined by route, tissue context, partner therapy, exposure schedule, and patient selection.
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