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

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 journal › Article › peer-review

98 Scopus citations

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.

Original language	English (US)
Pages (from-to)	115-128.e9
Journal	Immunity
Volume	55
Issue number	1
DOIs	https://doi.org/10.1016/j.immuni.2021.12.007
State	Published - Jan 11 2022
Externally published	Yes

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology
Infectious Diseases

Keywords

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

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10.1016/j.immuni.2021.12.007

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Chaurio, R. A., Anadon, C. M., Lee Costich, T., Payne, K. K., Biswas, S., Harro, C. M., Moran, C., Ortiz, A. C., Cortina, C., Rigolizzo, K. E., Sprenger, K. B., Mine, J. A., Innamarato, P., Mandal, G., Powers, J. J., Martin, A., Wang, Z., Mehta, S., Perez, B. A., ... Conejo-Garcia, J. R. (2022). TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures. Immunity, 55(1), 115-128.e9. https://doi.org/10.1016/j.immuni.2021.12.007

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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 = "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",

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Chaurio, RA, Anadon, CM, Lee Costich, T, Payne, KK, Biswas, S, Harro, CM, Moran, C, Ortiz, AC, Cortina, C, Rigolizzo, KE, Sprenger, KB, Mine, JA, Innamarato, P, Mandal, G, Powers, JJ, Martin, A, Wang, Z, Mehta, S, Perez, BA, Li, R, Robinson, J, Kroeger, JL, Curiel, TJ, Yu, X, Rodriguez, PC & Conejo-Garcia, JR 2022, 'TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures', Immunity, vol. 55, no. 1, pp. 115-128.e9. https://doi.org/10.1016/j.immuni.2021.12.007

TY - JOUR

T1 - TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures

AU - Chaurio, Ricardo A.

AU - Anadon, Carmen M.

AU - Lee Costich, Tara

AU - Payne, Kyle K.

AU - Biswas, Subir

AU - Harro, Carly M.

AU - Moran, Carlos

AU - Ortiz, Antonio C.

AU - Cortina, Carla

AU - Rigolizzo, Kristen E.

AU - Sprenger, Kimberly B.

AU - Mine, Jessica A.

AU - Innamarato, Patrick

AU - Mandal, Gunjan

AU - Powers, John J.

AU - Martin, Alexandra

AU - Wang, Zhitao

AU - Mehta, Sumit

AU - Perez, Bradford A.

AU - Li, Roger

AU - Robinson, John

AU - Kroeger, Jodi L.

AU - Curiel, Tyler J.

AU - Yu, Xiaoqing

AU - Rodriguez, Paulo C.

AU - Conejo-Garcia, Jose R.

PY - 2022/1/11

Y1 - 2022/1/11

N2 - 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.

AB - 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.

KW - B cell cancer

KW - SATB1

KW - T follicular helper cell

KW - immuno-oncology

KW - tertiary lymphoid structure

KW - tumor immunology

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UR - http://www.scopus.com/inward/citedby.url?scp=85122231113&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2021.12.007

DO - 10.1016/j.immuni.2021.12.007

M3 - Article

C2 - 35021053

AN - SCOPUS:85122231113

SN - 1074-7613

VL - 55

SP - 115-128.e9

JO - Immunity

JF - Immunity

IS - 1

ER -

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

Abstract

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