Anti-GITR Antibody Treatment Increases TCR Repertoire Diversity of Regulatory but not Effector T Cells Engaged in the Immune Response Against B16 Melanoma

Bozena Scirka, Edyta Szurek, Maciej Pietrzak, Grzegorz Rempala, Pawel Kisielow, Leszek Ignatowicz, Arkadiusz Miazek

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Crosslinking of glucocorticoid-induced TNF family-related receptor (GITR) with agonist antibodies restores cancer immunity by enhancing effector T cell (Teff) responses while interfering with intra-tumor regulatory T cell (Treg) stability and/or accumulation. However, how anti-GITR antibody infusion changes T cell receptor (TCR) repertoire of Teffs and Tregs engaged in anti-tumor immune response is unclear. Here, we used a transgenic mouse model (TCRmini) where T cells express naturally generated but limited TCR repertoire to trace the fate of individual T cells recognizing B16 melanoma in tumor-bearing mice, treated or non-treated with an anti-GITR monoclonal antibody DTA-1. Analysis of TCRs of CD4+ T cells from these mice revealed that the TCR repertoire of dominant tumor-reactive Teff clones remained rather similar in treated and non-treated mice. In contrast, both tumor-associated and peripheral TCR repertoire of Tregs, which were mostly distinct from that of Teffs, underwent DTA-1 mediated remodeling characterized by depletion of dominant clones and an emergence of more diverse, low-frequency clones bearing increased numbers of TCRs shared with Teffs. We conclude that the DTA-1 infusion eliminates activated Tregs engaged in the initial maintenance of tolerogenic niche for tumor growth, but over time, it favors tumor replenishment by Tregs expressing an array of TCRs able to compete with Teffs for recognition of the same tumor antigens which may prevent its complete eradication.

Original languageEnglish (US)
Pages (from-to)553-564
Number of pages12
JournalArchivum Immunologiae et Therapiae Experimentalis
Volume65
Issue number6
DOIs
StatePublished - Dec 1 2017

Fingerprint

Experimental Melanomas
T-Cell Antigen Receptor
Glucocorticoids
T-Lymphocytes
Antibodies
Neoplasms
Eragrostis
Clone Cells
Neoplasm Antigens
Regulatory T-Lymphocytes
Transgenic Mice
Immunity
Monoclonal Antibodies
Maintenance
Growth

Keywords

  • B16 melanoma
  • DTA-1
  • GITR
  • Immunotherapy
  • T regulatory cells
  • TCR diversity

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Anti-GITR Antibody Treatment Increases TCR Repertoire Diversity of Regulatory but not Effector T Cells Engaged in the Immune Response Against B16 Melanoma. / Scirka, Bozena; Szurek, Edyta; Pietrzak, Maciej; Rempala, Grzegorz; Kisielow, Pawel; Ignatowicz, Leszek; Miazek, Arkadiusz.

In: Archivum Immunologiae et Therapiae Experimentalis, Vol. 65, No. 6, 01.12.2017, p. 553-564.

Research output: Contribution to journalArticle

Scirka, Bozena ; Szurek, Edyta ; Pietrzak, Maciej ; Rempala, Grzegorz ; Kisielow, Pawel ; Ignatowicz, Leszek ; Miazek, Arkadiusz. / Anti-GITR Antibody Treatment Increases TCR Repertoire Diversity of Regulatory but not Effector T Cells Engaged in the Immune Response Against B16 Melanoma. In: Archivum Immunologiae et Therapiae Experimentalis. 2017 ; Vol. 65, No. 6. pp. 553-564.
@article{d7f7b454718a4ee09e935de644c7fa87,
title = "Anti-GITR Antibody Treatment Increases TCR Repertoire Diversity of Regulatory but not Effector T Cells Engaged in the Immune Response Against B16 Melanoma",
abstract = "Crosslinking of glucocorticoid-induced TNF family-related receptor (GITR) with agonist antibodies restores cancer immunity by enhancing effector T cell (Teff) responses while interfering with intra-tumor regulatory T cell (Treg) stability and/or accumulation. However, how anti-GITR antibody infusion changes T cell receptor (TCR) repertoire of Teffs and Tregs engaged in anti-tumor immune response is unclear. Here, we used a transgenic mouse model (TCRmini) where T cells express naturally generated but limited TCR repertoire to trace the fate of individual T cells recognizing B16 melanoma in tumor-bearing mice, treated or non-treated with an anti-GITR monoclonal antibody DTA-1. Analysis of TCRs of CD4+ T cells from these mice revealed that the TCR repertoire of dominant tumor-reactive Teff clones remained rather similar in treated and non-treated mice. In contrast, both tumor-associated and peripheral TCR repertoire of Tregs, which were mostly distinct from that of Teffs, underwent DTA-1 mediated remodeling characterized by depletion of dominant clones and an emergence of more diverse, low-frequency clones bearing increased numbers of TCRs shared with Teffs. We conclude that the DTA-1 infusion eliminates activated Tregs engaged in the initial maintenance of tolerogenic niche for tumor growth, but over time, it favors tumor replenishment by Tregs expressing an array of TCRs able to compete with Teffs for recognition of the same tumor antigens which may prevent its complete eradication.",
keywords = "B16 melanoma, DTA-1, GITR, Immunotherapy, T regulatory cells, TCR diversity",
author = "Bozena Scirka and Edyta Szurek and Maciej Pietrzak and Grzegorz Rempala and Pawel Kisielow and Leszek Ignatowicz and Arkadiusz Miazek",
year = "2017",
month = "12",
day = "1",
doi = "10.1007/s00005-017-0479-1",
language = "English (US)",
volume = "65",
pages = "553--564",
journal = "Archivum Immunologiae et Therapiae Experimentalis",
issn = "0004-069X",
publisher = "Birkhauser Verlag Basel",
number = "6",

}

TY - JOUR

T1 - Anti-GITR Antibody Treatment Increases TCR Repertoire Diversity of Regulatory but not Effector T Cells Engaged in the Immune Response Against B16 Melanoma

AU - Scirka, Bozena

AU - Szurek, Edyta

AU - Pietrzak, Maciej

AU - Rempala, Grzegorz

AU - Kisielow, Pawel

AU - Ignatowicz, Leszek

AU - Miazek, Arkadiusz

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Crosslinking of glucocorticoid-induced TNF family-related receptor (GITR) with agonist antibodies restores cancer immunity by enhancing effector T cell (Teff) responses while interfering with intra-tumor regulatory T cell (Treg) stability and/or accumulation. However, how anti-GITR antibody infusion changes T cell receptor (TCR) repertoire of Teffs and Tregs engaged in anti-tumor immune response is unclear. Here, we used a transgenic mouse model (TCRmini) where T cells express naturally generated but limited TCR repertoire to trace the fate of individual T cells recognizing B16 melanoma in tumor-bearing mice, treated or non-treated with an anti-GITR monoclonal antibody DTA-1. Analysis of TCRs of CD4+ T cells from these mice revealed that the TCR repertoire of dominant tumor-reactive Teff clones remained rather similar in treated and non-treated mice. In contrast, both tumor-associated and peripheral TCR repertoire of Tregs, which were mostly distinct from that of Teffs, underwent DTA-1 mediated remodeling characterized by depletion of dominant clones and an emergence of more diverse, low-frequency clones bearing increased numbers of TCRs shared with Teffs. We conclude that the DTA-1 infusion eliminates activated Tregs engaged in the initial maintenance of tolerogenic niche for tumor growth, but over time, it favors tumor replenishment by Tregs expressing an array of TCRs able to compete with Teffs for recognition of the same tumor antigens which may prevent its complete eradication.

AB - Crosslinking of glucocorticoid-induced TNF family-related receptor (GITR) with agonist antibodies restores cancer immunity by enhancing effector T cell (Teff) responses while interfering with intra-tumor regulatory T cell (Treg) stability and/or accumulation. However, how anti-GITR antibody infusion changes T cell receptor (TCR) repertoire of Teffs and Tregs engaged in anti-tumor immune response is unclear. Here, we used a transgenic mouse model (TCRmini) where T cells express naturally generated but limited TCR repertoire to trace the fate of individual T cells recognizing B16 melanoma in tumor-bearing mice, treated or non-treated with an anti-GITR monoclonal antibody DTA-1. Analysis of TCRs of CD4+ T cells from these mice revealed that the TCR repertoire of dominant tumor-reactive Teff clones remained rather similar in treated and non-treated mice. In contrast, both tumor-associated and peripheral TCR repertoire of Tregs, which were mostly distinct from that of Teffs, underwent DTA-1 mediated remodeling characterized by depletion of dominant clones and an emergence of more diverse, low-frequency clones bearing increased numbers of TCRs shared with Teffs. We conclude that the DTA-1 infusion eliminates activated Tregs engaged in the initial maintenance of tolerogenic niche for tumor growth, but over time, it favors tumor replenishment by Tregs expressing an array of TCRs able to compete with Teffs for recognition of the same tumor antigens which may prevent its complete eradication.

KW - B16 melanoma

KW - DTA-1

KW - GITR

KW - Immunotherapy

KW - T regulatory cells

KW - TCR diversity

UR - http://www.scopus.com/inward/record.url?scp=85021088702&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021088702&partnerID=8YFLogxK

U2 - 10.1007/s00005-017-0479-1

DO - 10.1007/s00005-017-0479-1

M3 - Article

VL - 65

SP - 553

EP - 564

JO - Archivum Immunologiae et Therapiae Experimentalis

JF - Archivum Immunologiae et Therapiae Experimentalis

SN - 0004-069X

IS - 6

ER -