Lymph node paracortex-inspired on-a-chip recapitulating immunosenescence: a cancer vaccine immunogenicity and antitumoral efficacy screening platform

Immunosenescence dramatically reduces cancer vaccine efficacy in elderly patients, who represent the majority of cancer cases. Despite this clinical reality, the age-related immune decline is rarely considered in preclinical testing. Therefore, novel <i>in vitro</i> models to test cancer vaccine efficacy, considering immunosenescence, are needed. Our novel lymph node paracortex-inspired on-a-chip (LNPoC) platform addresses this gap by recapitulating age-dependent immune responses against cancer vaccines, specifically antigen presentation, antigen-specific T cell activation, and antitumoral responses. Using this platform, we demonstrated that bone marrow-derived antigen-presenting cells (APCs) from young mice (6-7 weeks) displayed significantly enhanced ovalbumin (OVA) peptide presentation compared to APCs from older mice (35-36 weeks). This age-dependent difference translated to significantly greater OVA-specific CD8⁺ T cell activation and increased cytotoxicity against B16-OVA cancer cells. These age-dependent differences are unique to our LNPoC and undetectable in traditional 2D cultures, confirming that our LNPoC was more effective than 2D cultures at recapitulating immunosenescence-mediated immune responses against cancer vaccines <i>in vitro</i>. The <i>in vivo</i> validation confirms these findings, as young mice demonstrated higher OVA-specific CD8⁺ T cell responses and smaller tumors than older mice. Our LNPoC is a valuable tool for assessing immunosenescence's impact on cancer vaccines, potentially guiding more effective therapies for older adults.