@article{d0391cbeecba4bdc8399327d848a128c,
title = "TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures",
abstract = "The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes Tfh:B cell interactions and appropriate positioning within tissues. Here, we examined the impact of regulation of PD-1 expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4CreSatb1f/f mice enriched for antigen-specific Tfh cells, and TGF-β-mediated repression of SATB1 enhanced Tfh differentiation of human T cells. Mechanistically, high Icos expression in Satb1−/− CD4+ T cells promoted Tfh cell differentiation by preventing T follicular regulatory cell skewing and resulted in increased isotype-switched B cell responses in vivo. Ovarian tumors in CD4CreSatb1f/f mice accumulated tumor antigen-specific, LIGHT+CXCL13+IL-21+ Tfh cells and tertiary lymphoid structures (TLS). TLS formation decreased tumor growth in a CD4+ T cell and CXCL13-dependent manner. The transfer of Tfh cells, but not naive CD4+ T cells, induced TLS at tumor beds and decreased tumor growth. Thus, TGF-β-mediated silencing of Satb1 licenses Tfh cell differentiation, providing insight into the genesis of TLS within tumors.",
keywords = "B cell cancer, SATB1, T follicular helper cell, immuno-oncology, tertiary lymphoid structure, tumor immunology",
author = "Chaurio, {Ricardo A.} and Anadon, {Carmen M.} and {Lee Costich}, Tara and Payne, {Kyle K.} and Subir Biswas and Harro, {Carly M.} and Carlos Moran and Ortiz, {Antonio C.} and Carla Cortina and Rigolizzo, {Kristen E.} and Sprenger, {Kimberly B.} and Mine, {Jessica A.} and Patrick Innamarato and Gunjan Mandal and Powers, {John J.} and Alexandra Martin and Zhitao Wang and Sumit Mehta and Perez, {Bradford A.} and Roger Li and John Robinson and Kroeger, {Jodi L.} and Curiel, {Tyler J.} and Xiaoqing Yu and Rodriguez, {Paulo C.} and Conejo-Garcia, {Jose R.}",
note = "Funding Information: Support for Shared Resources was provided by Cancer Center Support Grant ( CCSG) CA076292 to H. Lee Moffitt Cancer Center. This study was supported by R01CA157664 , R01CA124515 , R01CA178687 , R01CA211913 , and U01CA232758 to J.R.C.-G. and R01CA184185 to P.C.R. K.K.P. was supported by T32CA009140 and The American Cancer Society Postdoctoral Fellowship . We are especially grateful to the Advanced Analytical and Digital Pathology (J. Nguyen), Flow Cytometry and Tissue Core Shared Resources at Moffitt Cancer Center, for exceptional support. We would like to thank the staff members of Comparative Medicine in the Stabile Research Building Vivarium for their husbandry and technical assistance. We also thanks to Johana Melendez, Jonathan Semidey-Hurtado, Mary Jane Perkins, Noel D. Clark, Neelkamal Chaudhary, and Haley E. Bruns for technical support. Funding Information: Support for Shared Resources was provided by Cancer Center Support Grant (CCSG) CA076292 to H. Lee Moffitt Cancer Center. This study was supported by R01CA157664, R01CA124515, R01CA178687, R01CA211913, and U01CA232758 to J.R.C.-G. and R01CA184185 to P.C.R. K.K.P. was supported by T32CA009140 and The American Cancer Society Postdoctoral Fellowship. We are especially grateful to the Advanced Analytical and Digital Pathology (J. Nguyen), Flow Cytometry and Tissue Core Shared Resources at Moffitt Cancer Center, for exceptional support. We would like to thank the staff members of Comparative Medicine in the Stabile Research Building Vivarium for their husbandry and technical assistance. We also thanks to Johana Melendez, Jonathan Semidey-Hurtado, Mary Jane Perkins, Noel D. Clark, Neelkamal Chaudhary, and Haley E. Bruns for technical support. R.A.C. designed, performed, and analyzed most of the experiments and co-wrote the manuscript; K.K.P. C.M.A. S.B. C.C.; G.M. J.J.P. T.L.C. P.I. A.M. and C.M.H. performed in vivo experiments, processed and stored clinical specimens and critically reviewed ongoing results and interpretations, as well as contributing to the preparation of the manuscript; A.C.O. performed the quantification of histological analyses, including the design of specific algorithms to quantify TLS, and contributed the analysis of experimental results; K.E.R. K.S. and J.A.M. performed in vivo treatments and provided technical guidance; C.M. performed multiplex immunohistochemistry experiments and supported the interpretation of the results; Z.W. and S.M. contributed the analysis of experimental results and the preparation of the manuscript; B.A.P. R.L. and T.J.C. provided clinical expertise, contributed to the design of the study and participated in the preparation of the manuscript; J.R. and J.L.K. optimized all flow cytometry panels, provided intellectual support, interpreted results, and contributed to experimental design; X.Y. performed all bioinformatical analyses and contributed to write the manuscript; P.C.R. contributed to the design of the study, participated in the interpretation of the results throughout all phases of the study and contributed to write the manuscript and design the experiments to respond to reviewers; and J.R.C.-G. oversaw and designed the study and experiments, analyzed data, and co-wrote the manuscript. J.R.C.-G. has stock options with Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics, receives honorarium from Anixa Biosciences, Alloy Therapeutics, and Leidos, and has sponsored research with Anixa Biosciences. R.L.: Clinical trial protocol committee?CG oncology; Scientific advisor/consultant?B.M.S. Ferring, Fergene, Arquer Diagnostics. B.A.P. has completed Advisory Board with AstraZeneca and has Research Support from B.M.S. J.R. is currently an employee of STEMCELL Technologies. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2022",
month = jan,
day = "11",
doi = "10.1016/j.immuni.2021.12.007",
language = "English (US)",
volume = "55",
pages = "115--128.e9",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "1",
}