Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts
| Autor: | Robin S. Lindsay, Max O. Meneveau, Yang Xin Fu, Anthony B. Rodriguez, J. David Peske, Salwador Cyranowski, Geoffrey Parriott, Amber N. Woods, Mark R. Conaway, Victor H. Engelhard, Katie M. Leick, Marit M. Melssen, Craig L. Slingluff, S. Young, Ileana S. Mauldin |
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| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_treatment
Inflammation Biology CD8-Positive T-Lymphocytes Lymphocyte Activation General Biochemistry Genetics and Molecular Biology Receptors Tumor Necrosis Factor Article Cancer immunotherapy Cancer-Associated Fibroblasts Lymphotoxin beta Receptor Neoplasms medicine Cytotoxic T cell Animals Humans B cell Cell Proliferation B-Lymphocytes Membrane Glycoproteins Cancer Cell Differentiation Immunotherapy medicine.disease Immune checkpoint Mice Inbred C57BL medicine.anatomical_structure Lymphatic system Tertiary Lymphoid Structures Reticular connective tissue Cancer research medicine.symptom Peritoneum Lymphotoxin beta receptor Checkpoint Blockade Immunotherapy Signal Transduction |
| Zdroj: | Cell reports |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY 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. Graphical Abstract In brief 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. |
| Databáze: | OpenAIRE |
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