Antigen cross-presentation in young tumor-bearing hosts promotes CD8 T cell terminal differentiation [WGBS]

ABSTRACT: The immune system undergoes a progressive functional remodeling with age, polarizing the immune responses toward a “killer” or “healer” phenotype. Understanding how the age bias shapes anti-tumor immunity is essential in designing effective immunotherapies. In this manuscript we explore the anti-tumor CD8+ T cell responses generated in young (prepubescent) and adult (pre-senescent) mice. Using an MHCI-deficient, trackable tumor model, we observed that tumor reactive CD8+ T cells that expanded in young tumor-bearing (TB) mice acquired a terminally differentiated phenotype characterized by overexpression of inhibitory receptors and the transcription factor Tox1. Furthermore, tumor infiltrating CD8+ T cells from young tumors yielded a poor cytokine response compared to CD8+ T cells infiltrating adult tumors. Young migratory dendritic cells (migDC) and mononuclear phagocytic cells (MPCs) infiltrating young tumors were more competent in capturing and cross-presenting tumor antigen, leading to enhanced priming of CD8+ T cells in the draining lymph nodes (dLNs), and their subsequent terminal differentiation in the tumors. Notably, single-cell transcriptional profiling of tumor infiltrating MPCs revealed that young MPCs are polarized toward an inflammatory, effector phenotype. Consistent with our observations in young vs adult TB mice, analysis of immune infiltrates from pediatric solid tumors revealed a significant correlation between tumor-infiltrating CD8+ T cells with an exhaustion phenotype and the frequency of PD-L1-expressing phagocytic cells. Collectively, these data indicate that the young microenvironment of an actively developing tissue contributes to the generation of an immune response skewed toward a terminal effector state, thus narrowing the window for immunotherapeutic interventions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188388 | GEO | 2022/02/28

REPOSITORIES: GEO