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.
Original language | English (US) |
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Article number | 109422 |
Journal | Cell Reports |
Volume | 36 |
Issue number | 3 |
DOIs | |
State | Published - Jul 20 2021 |
Externally published | Yes |
Keywords
- B lymphocytes
- B16 melanoma
- cancer-associated fibroblasts
- CD8 T lymphocytes
- 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
- General Biochemistry, Genetics and Molecular Biology