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

Anthony B. Rodriguez, J. David Peske, Amber N. Woods, Katie M. Leick, Ileana S. Mauldin, Max O. Meneveau, Samuel J. Young, Robin S. Lindsay, Marit M. Melssen, Salwador Cyranowski, Geoffrey Parriott, Mark R. Conaway, Yang Xin Fu, Craig L. Slingluff, Victor H. Engelhard

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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-α1β2. 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.

Original languageEnglish (US)
Article number109422
JournalCell Reports
Issue number3
StatePublished - Jul 20 2021


  • B lymphocytes
  • B16 melanoma
  • CD8 T lymphocytes
  • cancer-associated fibroblasts
  • checkpoint blockade immunotherapy
  • lymphoid tissue inducer cell
  • lymphoid tissue organizer cell
  • lymphotoxin-β receptor
  • tertiary lymphoid structure
  • tumor necrosis factor receptor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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