Adjuvant IL-7 potentiates adoptive T cell therapy by amplifying and sustaining polyfunctional antitumor CD4+ T cells

Zhi-Chun Ding, Tsadik Habtetsion, Yang Cao, Tao Li, Chufeng Liu, Michal Kuczma, Tingting Chen, Zhonglin Hao, Locke Johnson Bryan, David H Munn, Gang Zhou

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Increased availability of homeostatic cytokines is considered a major mechanism by which lymphodepletion enhances the efficacy of adoptive T cell therapy (ACT). IL-7 is one such cytokine capable of augmenting the function of tumor-reactive CD8+ T cells. However, whether host-derived IL-7 plays a role in driving the proper function of CD4+ T cells in an ACT setting remains unclear. Here we report that lymphodepleting chemotherapy by cyclophosphamide (CTX) does not lead to increased availability of the endogenous IL-7 in mice. Despite of a paucity of IL-7 in the immune milieu, CTX preconditioning allowed adoptively transferred naïve tumor-specific CD4+ T cells to undergo effector differentiation and regain IL-7Rα expression, giving rise to IL-7-responsive polyfunctional CD4+ effector cells. Correspondingly, supplementation of exogenous recombinant IL-7 markedly amplified and sustained polyfunctional CD4+ effector cells, resulting in improved therapeutic outcome in a mouse lymphoma model. We further demonstrated that the immune-enhancing effects of IL-7 were also applicable to donor CD4+ T cells pre-activated under Th1 polarizing condition. These findings suggest caution in relying on the endogenous IL-7 to enhance donor T cell expansion and persistence after lymphodepleting chemotherapy, and highlight the usefulness of recombinant IL-7 as an adjuvant for adoptive immunotherapy.

Original languageEnglish (US)
Article number12168
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Interleukin-7
Cell- and Tissue-Based Therapy
T-Lymphocytes
Cytokines
Adoptive Immunotherapy
Drug Therapy
Cyclophosphamide
Lymphoma
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Adjuvant IL-7 potentiates adoptive T cell therapy by amplifying and sustaining polyfunctional antitumor CD4+ T cells. / Ding, Zhi-Chun; Habtetsion, Tsadik; Cao, Yang; Li, Tao; Liu, Chufeng; Kuczma, Michal; Chen, Tingting; Hao, Zhonglin; Bryan, Locke Johnson; Munn, David H; Zhou, Gang.

In: Scientific Reports, Vol. 7, No. 1, 12168, 01.12.2017.

Research output: Contribution to journalArticle

Ding, Zhi-Chun ; Habtetsion, Tsadik ; Cao, Yang ; Li, Tao ; Liu, Chufeng ; Kuczma, Michal ; Chen, Tingting ; Hao, Zhonglin ; Bryan, Locke Johnson ; Munn, David H ; Zhou, Gang. / Adjuvant IL-7 potentiates adoptive T cell therapy by amplifying and sustaining polyfunctional antitumor CD4+ T cells. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
@article{05c16a9425c84255b3d5da799dc4fdd0,
title = "Adjuvant IL-7 potentiates adoptive T cell therapy by amplifying and sustaining polyfunctional antitumor CD4+ T cells",
abstract = "Increased availability of homeostatic cytokines is considered a major mechanism by which lymphodepletion enhances the efficacy of adoptive T cell therapy (ACT). IL-7 is one such cytokine capable of augmenting the function of tumor-reactive CD8+ T cells. However, whether host-derived IL-7 plays a role in driving the proper function of CD4+ T cells in an ACT setting remains unclear. Here we report that lymphodepleting chemotherapy by cyclophosphamide (CTX) does not lead to increased availability of the endogenous IL-7 in mice. Despite of a paucity of IL-7 in the immune milieu, CTX preconditioning allowed adoptively transferred na{\"i}ve tumor-specific CD4+ T cells to undergo effector differentiation and regain IL-7Rα expression, giving rise to IL-7-responsive polyfunctional CD4+ effector cells. Correspondingly, supplementation of exogenous recombinant IL-7 markedly amplified and sustained polyfunctional CD4+ effector cells, resulting in improved therapeutic outcome in a mouse lymphoma model. We further demonstrated that the immune-enhancing effects of IL-7 were also applicable to donor CD4+ T cells pre-activated under Th1 polarizing condition. These findings suggest caution in relying on the endogenous IL-7 to enhance donor T cell expansion and persistence after lymphodepleting chemotherapy, and highlight the usefulness of recombinant IL-7 as an adjuvant for adoptive immunotherapy.",
author = "Zhi-Chun Ding and Tsadik Habtetsion and Yang Cao and Tao Li and Chufeng Liu and Michal Kuczma and Tingting Chen and Zhonglin Hao and Bryan, {Locke Johnson} and Munn, {David H} and Gang Zhou",
year = "2017",
month = "12",
day = "1",
doi = "10.1038/s41598-017-12488-z",
language = "English (US)",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Adjuvant IL-7 potentiates adoptive T cell therapy by amplifying and sustaining polyfunctional antitumor CD4+ T cells

AU - Ding, Zhi-Chun

AU - Habtetsion, Tsadik

AU - Cao, Yang

AU - Li, Tao

AU - Liu, Chufeng

AU - Kuczma, Michal

AU - Chen, Tingting

AU - Hao, Zhonglin

AU - Bryan, Locke Johnson

AU - Munn, David H

AU - Zhou, Gang

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Increased availability of homeostatic cytokines is considered a major mechanism by which lymphodepletion enhances the efficacy of adoptive T cell therapy (ACT). IL-7 is one such cytokine capable of augmenting the function of tumor-reactive CD8+ T cells. However, whether host-derived IL-7 plays a role in driving the proper function of CD4+ T cells in an ACT setting remains unclear. Here we report that lymphodepleting chemotherapy by cyclophosphamide (CTX) does not lead to increased availability of the endogenous IL-7 in mice. Despite of a paucity of IL-7 in the immune milieu, CTX preconditioning allowed adoptively transferred naïve tumor-specific CD4+ T cells to undergo effector differentiation and regain IL-7Rα expression, giving rise to IL-7-responsive polyfunctional CD4+ effector cells. Correspondingly, supplementation of exogenous recombinant IL-7 markedly amplified and sustained polyfunctional CD4+ effector cells, resulting in improved therapeutic outcome in a mouse lymphoma model. We further demonstrated that the immune-enhancing effects of IL-7 were also applicable to donor CD4+ T cells pre-activated under Th1 polarizing condition. These findings suggest caution in relying on the endogenous IL-7 to enhance donor T cell expansion and persistence after lymphodepleting chemotherapy, and highlight the usefulness of recombinant IL-7 as an adjuvant for adoptive immunotherapy.

AB - Increased availability of homeostatic cytokines is considered a major mechanism by which lymphodepletion enhances the efficacy of adoptive T cell therapy (ACT). IL-7 is one such cytokine capable of augmenting the function of tumor-reactive CD8+ T cells. However, whether host-derived IL-7 plays a role in driving the proper function of CD4+ T cells in an ACT setting remains unclear. Here we report that lymphodepleting chemotherapy by cyclophosphamide (CTX) does not lead to increased availability of the endogenous IL-7 in mice. Despite of a paucity of IL-7 in the immune milieu, CTX preconditioning allowed adoptively transferred naïve tumor-specific CD4+ T cells to undergo effector differentiation and regain IL-7Rα expression, giving rise to IL-7-responsive polyfunctional CD4+ effector cells. Correspondingly, supplementation of exogenous recombinant IL-7 markedly amplified and sustained polyfunctional CD4+ effector cells, resulting in improved therapeutic outcome in a mouse lymphoma model. We further demonstrated that the immune-enhancing effects of IL-7 were also applicable to donor CD4+ T cells pre-activated under Th1 polarizing condition. These findings suggest caution in relying on the endogenous IL-7 to enhance donor T cell expansion and persistence after lymphodepleting chemotherapy, and highlight the usefulness of recombinant IL-7 as an adjuvant for adoptive immunotherapy.

UR - http://www.scopus.com/inward/record.url?scp=85029750235&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029750235&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-12488-z

DO - 10.1038/s41598-017-12488-z

M3 - Article

C2 - 28939858

AN - SCOPUS:85029750235

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 12168

ER -