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

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 ^Cre Satb1 ^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 ^Cre Satb1 ^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.
Competing Interests: Declaration of interests 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.
(Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)