Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts.

Tumor-associated tertiary lymphoid structures (TA-TLS) are associated with enhanced patient survival and responsiveness to cancer therapies, but the mechanisms underlying their development are unknown. We show here that TA-TLS development in murine melanoma is orchestrated by cancer-associated fibroblasts (CAF) with characteristics of lymphoid tissue organizer cells that are induced by tumor necrosis factor receptor signaling. CAF organization into reticular networks is mediated by CD8 T cells, while CAF accumulation and TA-TLS expansion depend on CXCL13-mediated recruitment of B cells expressing lymphotoxin-α 1 β 2. Some of these elements are also overrepresented in human TA-TLS. Additionally, we demonstrate that immunotherapy induces more and larger TA-TLS that are more often organized with discrete T and B cell zones, and that TA-TLS presence, number, and size are correlated with reduced tumor size and overall response to checkpoint immunotherapy. This work provides a platform for manipulating TA-TLS development as a cancer immunotherapy strategy. [Display omitted] • Cancer-associated fibroblasts orchestrate tertiary lymphoid structures in tumors • CD8 T cells and B cells drive tertiary lymphoid structure development via fibroblasts • Tertiary lymphoid structure development is mediated by TNF and lymphotoxin receptors • Checkpoint blockade alters tertiary lymphoid structures together with tumor control Rodriguez et al. describe the cellular and molecular mechanisms driving development of tumor-associated tertiary lymphoid structures and the importance of these structures as mediators of anti-tumor immunity and response to checkpoint immunotherapy. [ABSTRACT FROM AUTHOR]