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

• DOI: 10.1016/j.immuni.2021.12.007
• Publication Date: 2022-01-11T15:51:35Z
• Authors: 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-Ga...
• Keywords: Mice, Knockout; 0301 basic medicine; Genotype; Programmed Cell Death 1 Receptor; Cell Differentiation; Matrix Attachment Region Binding Proteins; T-Lymphocytes, Helper-Inducer; Germinal Center; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Lymphocytes, Tumor-Infiltrating; Tertiary Lymphoid Structures; Gene Expression Regulation; Transforming Growth Factor beta; Animals; Gene Silencing

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.