Age-dependent tumor-immune interactions underlie immunotherapy response in pediatric cancer

Pediatric cancers originate in rapidly growing tissues within the context of a developing host. However, the interactions between cancer cells and the developing immune system are incompletely understood. Here, we established a suite of pediatric syngeneic mouse cancer models across diverse anatomical sites and compared their tumor immune microenvironment with that in adult mice. Tumors in pediatric mice exhibited significantly accelerated growth and diminished leukocyte infiltration, dominated by naïve-like PD-1 ^low /CD8 ⁺ T cells, and proliferative MHCII ^low /PD-L1 ^hi /CD86 ^low macrophages. Tumor-infiltrating leukocytes in pediatric mice were enriched for MYC targets, which was also observed in pediatric patient samples. Furthermore, pediatric mice displayed poor responses to anti-PD-1/PD-L1 or bispecific T cell engager antibodies, which could be reversed by inducing a proinflammatory microenvironment via MYC inhibition or inducing macrophage polarization to an MHCII ^hi phenotype. These findings underscore the significant influence of young age on cancer immune responses and reveal potential new therapeutic opportunities for pediatric cancers.