TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures

Ricardo A. Chaurio, Carmen M. Anadon, Tara Lee Costich, Kyle K. Payne, Subir Biswas, Carly M. Harro, Carlos Moran, Antonio C. Ortiz, Carla Cortina, Kristen E. Rigolizzo, Kimberly B. Sprenger, Jessica A. Mine, Patrick Innamarato, Gunjan Mandal, John J. Powers, Alexandra Martin, Zhitao Wang, Sumit Mehta, Bradford A. Perez, Roger LiJohn Robinson, Jodi L. Kroeger, Tyler J. Curiel, Xiaoqing Yu, Paulo C. Rodriguez, Jose R. Conejo-Garcia

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)115-128.e9
JournalImmunity
Volume55
Issue number1
DOIs
StatePublished - Jan 11 2022

Keywords

  • B cell cancer
  • SATB1
  • T follicular helper cell
  • immuno-oncology
  • tertiary lymphoid structure
  • tumor immunology

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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