Formation of tertiary lymphoid structures drives Parkin antitumor immunity.

Abstract

Mitochondria activate immunity, but the role in cancer is unknown. Here, we report that transgenic expression of Parkin, a regulator of mitochondrial fitness, induces inflammation and interferon (IFN) gene signatures, suppresses prostate cancer formation and generates CD8⁺ and CD20⁺ intraprostatic immune aggregates. These had hallmarks of mature tertiary lymphoid structures (TLS), expressing markers of B cell maturation (CXCL13, CCL21), germinal center formation (BCL6, GL7), mature dendritic cells (MHC-II/CD208) and high endothelial venules (LYVE-1). Parkin TLS showed high Ig gene expression, recruitment of CXCR5⁺ follicular T helper cells and expansion of CD69⁺/KLRG1⁺ effector T cells. Conditioned medium from Parkin-positive cells expanded memory B and plasma cells, increased IgG1 production, and sustained B and T cell migration. Finally, conditional expression of Parkin induced TLS formation, upregulated Ig chains and inhibited prostate cancer growth, in vivo, whereas Parkin reconstitution in IFNAR1, CD8 or CD20 knockout mice had no effect. Therefore, mitochondrial immunity orchestrates antitumor responses, and TLS formation contributes to tumor suppression.