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 Li; John Robinson; Jodi L Kroeger; Tyler J Curiel; Xiaoqing Yu; Paulo C Rodriguez; Jose R Conejo-Garcia

doi:10.1016/j.immuni.2021.12.007

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

Immunity. 2022 Jan 11;55(1):115-128.e9. doi: 10.1016/j.immuni.2021.12.007.

Authors

Ricardo A Chaurio¹, Carmen M Anadon¹, Tara Lee Costich¹, Kyle K Payne¹, Subir Biswas¹, Carly M Harro¹, Carlos Moran², Antonio C Ortiz³, Carla Cortina¹, Kristen E Rigolizzo¹, Kimberly B Sprenger¹, Jessica A Mine¹, Patrick Innamarato¹, Gunjan Mandal¹, John J Powers¹, Alexandra Martin⁴, Zhitao Wang¹, Sumit Mehta⁴, Bradford A Perez⁵, Roger Li⁶, John Robinson⁷, Jodi L Kroeger⁷, Tyler J Curiel⁸, Xiaoqing Yu⁹, Paulo C Rodriguez¹, Jose R Conejo-Garcia¹⁰

Affiliations

¹ Departments of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
² Departments of Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
³ Departments of Analytic Microscopy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁴ Departments of Gynecologic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁵ Departments of Radiation Therapy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁶ Departments of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁷ Departments of Flow Cytometry Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁸ Mays Cancer Center, University of Texas Health, San Antonio, TX 78229, USA.
⁹ Departments of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
¹⁰ Departments of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Departments of Gynecologic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Departments of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: [email protected].

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 CD4^CreSatb1^f/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 CD4^CreSatb1^f/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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Gene Expression Regulation
Gene Silencing
Genotype
Germinal Center / immunology*
Lymphocytes, Tumor-Infiltrating / immunology*
Matrix Attachment Region Binding Proteins / genetics
Matrix Attachment Region Binding Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / metabolism
T-Lymphocytes, Helper-Inducer / immunology*
Tertiary Lymphoid Structures / immunology*
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism*

Substances

Matrix Attachment Region Binding Proteins
Pdcd1 protein, mouse
Programmed Cell Death 1 Receptor
Satb1 protein, mouse
Transforming Growth Factor beta

Abstract

Publication types

MeSH terms

Substances

Grants and funding