CXCL9 and CXCL13 coordinately shape the immune-activated microenvironment of endometrial cancer via tertiary lymphoid structure formation

Abstract Immune checkpoint inhibitor (ICI) therapy has been successfully applied to various cancers; however, not all patients respond to ICI therapy. Tumors with an immune-activated environment are more responsive to ICIs. To identify the cells and molecules essential to the formation of an immune-activated cancer microenvironment, we focused on the tertiary lymphoid structure (TLS) and performed histological and genomic analyses using endometrial cancer material. In the high immunogenic group, numerous TLSs were observed and CXCL9 and CXCL13 expression levels were markedly increased. We established that CXCL9-positive antigen-presenting and CXCL13-positive follicular dendritic cells were distributed in the T and B cell zone of TLS, respectively. A group of molecules upregulated along with CXCL9 and CXCL13 expression were strongly associated with cellular immunity. These results suggest that CXCL9-expressing antigen-presenting cells and CXCL13-expressing follicular dendritic cells coordinately shape the immune-activated microenvironment through TLS formation.