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

Abstract

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.