Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma

Justin Kline, Ian Elliott Brown, Yuan Yuan Zha, Christian Blank, John Strickler, Harald Wouters, Long Zhang, Thomas F. Gajewski

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Purpose: To investigate the antitumor efficacy of T-cell anergy reversal through homeostatic proliferation and regulatory T-cell (Treg) depletion in a clinically relevant murine adoptive immunotherapy model. Experimental Design: B16 melanoma cells were engineered to express the model SIYRYYGL (SIY) antigen to enable immune monitoring. Tumor-specificTcells expanded in tumor-challenged wild-type hosts but became hyporesponsive.To examine whether lymphopenia-induced homeostatic proliferation could reverse tumor-induced T-cell anergy, total splenicTcells were transferred into lymphopenic RAG2-/- mice or control P14/RAG2-/- mice. Tumor growth was measured, and SlY-specific immune responses were monitored using ELISPOT and SIY/Kb tetramers. To determine whether Treg depletion could synergize with homeostatic proliferation, RAG2-/- mice received total or CD25-depleted T cells, followed or preceded by B16.SIY challenge. This approach was further investigated in wild-type mice lymphodepleted with sublethal total body irradiation. Results: Adoptive transfer of total splenic T cells into RAG2 -/- mice moderately affected the growth rate of B16.SIY. As Treg expansion occurred in tumor-bearing mice, CD25+ T cells were depleted from total Tcells before adoptive transfer. Interestingly, transfer of CD25-depleted T cells into RAG 2-/- mice resulted in potent rejection of B16 melanoma in both prophylactic and short-term preimplanted tumor settings and was associated with maintained T-cell effector function. Using a clinically applicable approach, wild-type mice were lymphodepleted using sublethal total body irradiation, which similarly supported tumor rejection upon transfer of CD25-depleted Tcells. Conclusions: Our results indicate that combined CD25 depletion and homeostatic proliferation support a potent antitumor immune response - an approach with potential for clinical translation.

Original languageEnglish (US)
Pages (from-to)3156-3167
Number of pages12
JournalClinical Cancer Research
Volume14
Issue number10
DOIs
StatePublished - May 15 2008
Externally publishedYes

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Experimental Melanomas
Regulatory T-Lymphocytes
T-Lymphocytes
Neoplasms
Adoptive Transfer
Whole-Body Irradiation
Adoptive Immunotherapy
Enzyme-Linked Immunospot Assay
Immunologic Monitoring
Lymphopenia
Growth
Research Design
Antigens
superagonist SIYR

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma. / Kline, Justin; Brown, Ian Elliott; Zha, Yuan Yuan; Blank, Christian; Strickler, John; Wouters, Harald; Zhang, Long; Gajewski, Thomas F.

In: Clinical Cancer Research, Vol. 14, No. 10, 15.05.2008, p. 3156-3167.

Research output: Contribution to journalArticle

Kline, J, Brown, IE, Zha, YY, Blank, C, Strickler, J, Wouters, H, Zhang, L & Gajewski, TF 2008, 'Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma', Clinical Cancer Research, vol. 14, no. 10, pp. 3156-3167. https://doi.org/10.1158/1078-0432.CCR-07-4696
Kline, Justin ; Brown, Ian Elliott ; Zha, Yuan Yuan ; Blank, Christian ; Strickler, John ; Wouters, Harald ; Zhang, Long ; Gajewski, Thomas F. / Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 10. pp. 3156-3167.
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AU - Kline, Justin

AU - Brown, Ian Elliott

AU - Zha, Yuan Yuan

AU - Blank, Christian

AU - Strickler, John

AU - Wouters, Harald

AU - Zhang, Long

AU - Gajewski, Thomas F.

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N2 - Purpose: To investigate the antitumor efficacy of T-cell anergy reversal through homeostatic proliferation and regulatory T-cell (Treg) depletion in a clinically relevant murine adoptive immunotherapy model. Experimental Design: B16 melanoma cells were engineered to express the model SIYRYYGL (SIY) antigen to enable immune monitoring. Tumor-specificTcells expanded in tumor-challenged wild-type hosts but became hyporesponsive.To examine whether lymphopenia-induced homeostatic proliferation could reverse tumor-induced T-cell anergy, total splenicTcells were transferred into lymphopenic RAG2-/- mice or control P14/RAG2-/- mice. Tumor growth was measured, and SlY-specific immune responses were monitored using ELISPOT and SIY/Kb tetramers. To determine whether Treg depletion could synergize with homeostatic proliferation, RAG2-/- mice received total or CD25-depleted T cells, followed or preceded by B16.SIY challenge. This approach was further investigated in wild-type mice lymphodepleted with sublethal total body irradiation. Results: Adoptive transfer of total splenic T cells into RAG2 -/- mice moderately affected the growth rate of B16.SIY. As Treg expansion occurred in tumor-bearing mice, CD25+ T cells were depleted from total Tcells before adoptive transfer. Interestingly, transfer of CD25-depleted T cells into RAG 2-/- mice resulted in potent rejection of B16 melanoma in both prophylactic and short-term preimplanted tumor settings and was associated with maintained T-cell effector function. Using a clinically applicable approach, wild-type mice were lymphodepleted using sublethal total body irradiation, which similarly supported tumor rejection upon transfer of CD25-depleted Tcells. Conclusions: Our results indicate that combined CD25 depletion and homeostatic proliferation support a potent antitumor immune response - an approach with potential for clinical translation.

AB - Purpose: To investigate the antitumor efficacy of T-cell anergy reversal through homeostatic proliferation and regulatory T-cell (Treg) depletion in a clinically relevant murine adoptive immunotherapy model. Experimental Design: B16 melanoma cells were engineered to express the model SIYRYYGL (SIY) antigen to enable immune monitoring. Tumor-specificTcells expanded in tumor-challenged wild-type hosts but became hyporesponsive.To examine whether lymphopenia-induced homeostatic proliferation could reverse tumor-induced T-cell anergy, total splenicTcells were transferred into lymphopenic RAG2-/- mice or control P14/RAG2-/- mice. Tumor growth was measured, and SlY-specific immune responses were monitored using ELISPOT and SIY/Kb tetramers. To determine whether Treg depletion could synergize with homeostatic proliferation, RAG2-/- mice received total or CD25-depleted T cells, followed or preceded by B16.SIY challenge. This approach was further investigated in wild-type mice lymphodepleted with sublethal total body irradiation. Results: Adoptive transfer of total splenic T cells into RAG2 -/- mice moderately affected the growth rate of B16.SIY. As Treg expansion occurred in tumor-bearing mice, CD25+ T cells were depleted from total Tcells before adoptive transfer. Interestingly, transfer of CD25-depleted T cells into RAG 2-/- mice resulted in potent rejection of B16 melanoma in both prophylactic and short-term preimplanted tumor settings and was associated with maintained T-cell effector function. Using a clinically applicable approach, wild-type mice were lymphodepleted using sublethal total body irradiation, which similarly supported tumor rejection upon transfer of CD25-depleted Tcells. Conclusions: Our results indicate that combined CD25 depletion and homeostatic proliferation support a potent antitumor immune response - an approach with potential for clinical translation.

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