IL-15 trans-presentation at the innate-adaptive interface: mechanisms and translation in cancer immunotherapy

Abstract

ABSTRACT 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.