Skip to Content
Merck
  • Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts.

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

Cell reports (2021-07-22)
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
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-FAP Antibody, clone 73.3, clone 73.3, from mouse
Roche
DAPI, 4′,6-Diamidine-2′-phenylindole dihydrochloride
Roche
DNase I, from bovine pancreas