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 language | English (US) |
|---|---|
| Pages (from-to) | 3156-3167 |
| Number of pages | 12 |
| Journal | Clinical Cancer Research |
| Volume | 14 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 15 2008 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma
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.
PY - 2008/5/15
Y1 - 2008/5/15
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.
UR - http://www.scopus.com/inward/record.url?scp=49649121241&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=49649121241&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-07-4696
DO - 10.1158/1078-0432.CCR-07-4696
M3 - Article
C2 - 18483384
AN - SCOPUS:49649121241
VL - 14
SP - 3156
EP - 3167
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 10
ER -