Immune Mechanisms Orchestrate Tertiary Lymphoid Structures in Tumors Via Cancer-Associated Fibroblasts

Tertiary lymphoid structures (TLS) are lymphoid aggregates resembling secondary lymphoid organs found at sites of inflammation. TLS have been identified in tumors (TA-TLS), where they are associated with enhanced patient survival, but the mechanisms underlying their formation are unknown. We show here that TA-TLS development in murine melanomas is orchestrated by fibroblasts with characteristics of lymphoid tissue organizer cells that are induced by tumor necrosis factor receptor signaling. Fibroblast organization into reticular networks is initiated by CD8 T-cells, but full TA-TLS development depends on CXCL13-mediated recruitment of B-cells that express lymphotoxin-α1/β2. Some of these elements were also overrepresented in TA-TLS of human tumors. Immune checkpoint blockade induced more and larger TA-TLS that were more often organized with discrete T- and B-cell zones. This work provides a platform for manipulating TA-TLS as a cancer immunotherapy strategy.