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

SUMMARY 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. HIGHLIGHTS Allograft tumors exhibit markedly accelerated growth in pediatric hosts compared to adults. Tumors growing in pediatric mice have reduced leukocyte infiltration, dominated by naïve-like PD-1 low /CD8 + T cells, and MHCII low /M2-like macrophages. Enrichment of MYC target genes is observed in pediatric mouse tumors and confirmed in primary patient tumor samples. Pediatric mice display reduced response to anti-PD-1/PD-L1 and BiTE immunotherapy, which can be reversed by remodeling the TIME, using either MYC inhibition or macrophage polarization.