Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma.
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-specific T cells 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 splenic T cells were transferred into lymphopenic RAG2-/- mice or control P14/RAG2-/- mice. Tumor growth was measured, and SIY-specific immune responses were monitored using ELISPOT and SIY/K(b) 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 T cells before adoptive transfer. Interestingly, transfer of CD25-depleted T cells into RAG2-/- 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 T cells. CONCLUSIONS: Our results indicate that combined CD25 depletion and homeostatic proliferation support a potent antitumor immune response--an approach with potential for clinical translation.
Kline, J; Brown, IE; Zha, Y-Y; Blank, C; Strickler, J; Wouters, H; Zhang, L; Gajewski, TF
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