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

Cell Rep. 2021 Jul 20;36(3):109422. doi: 10.1016/j.celrep.2021.109422.


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.

Keywords: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer-Associated Fibroblasts / pathology*
  • Cell Differentiation
  • Cell Proliferation
  • Humans
  • Immunotherapy
  • Lymphocyte Activation / immunology
  • Lymphotoxin beta Receptor / metabolism
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / immunology*
  • Neoplasms / pathology*
  • Neoplasms / therapy
  • Peritoneum / pathology
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction
  • Tertiary Lymphoid Structures / immunology*


  • Lymphotoxin beta Receptor
  • Membrane Glycoproteins
  • PDPN protein, human
  • Receptors, Tumor Necrosis Factor