@article{0466efdb94e8456bbff1284b19055575,
title = "Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts",
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.",
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",
author = "Rodriguez, {Anthony B.} and Peske, {J. David} and Woods, {Amber N.} and Leick, {Katie M.} and Mauldin, {Ileana S.} and Meneveau, {Max O.} and Young, {Samuel J.} and Lindsay, {Robin S.} and Melssen, {Marit M.} and Salwador Cyranowski and Geoffrey Parriott and Conaway, {Mark R.} and Fu, {Yang Xin} and Slingluff, {Craig L.} and Engelhard, {Victor H.}",
note = "Funding Information: We thank the Engelhard and Dudley labs for discussion and suggestions. This work was supported by USPHS Grants CA78400 and CA181794 (to V.H.E.) and the University of Virginia Cancer Center Schiff Foundation (to C.L.S. and I.S.M.). The University of Virginia Histology and Flow Cytometry Cores are supported by USPHS Grant P30 CA44579. A.B.R. and A.N.W. were supported by USPHS Training Grant AI007496, J.D.P. by USPHS Training Grant GM007267, and K.M.L. by USPHS Training Grant CA163177. J.D.P. was the recipient of a Farrow Fellowship, and A.B.R. was the recipient of a Wagner Fellowship, both from the University of Virginia. Murine experiments were performed and analyzed by A.B.R. J.D.P. A.N.W. K.M.L. M.M.M. R.S.L. S.C. and G.P. Murine IF analysis was performed by R.S.L. Multispectral imaging was performed and analyzed by K.M.L. I.S.M. S.J.Y. and A.B.R. Statistical analysis of human multispectral imaging data was done by M.O.M. and M.R.C. V.H.E. and C.L.S. supervised experimental design and data interpretation. All authors contributed to manuscript preparation. The authors declare no competing interests. Funding Information: We thank the Engelhard and Dudley labs for discussion and suggestions. This work was supported by USPHS Grants CA78400 and CA181794 (to V.H.E.) and the University of Virginia Cancer Center Schiff Foundation (to C.L.S. and I.S.M.). The University of Virginia Histology and Flow Cytometry Cores are supported by USPHS Grant P30 CA44579 . A.B.R. and A.N.W. were supported by USPHS Training Grant AI007496 , J.D.P. by USPHS Training Grant GM007267 , and K.M.L. by USPHS Training Grant CA163177 . J.D.P. was the recipient of a Farrow Fellowship , and A.B.R. was the recipient of a Wagner Fellowship , both from the University of Virginia . Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = jul,
day = "20",
doi = "10.1016/j.celrep.2021.109422",
language = "English (US)",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}