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Homeostatic Proliferation Plus Regulatory T-Cell Depletion Promotes Potent Rejection of B16 Melanoma

Authors' Affiliations: ¹ Department of Medicine and ² Department of Pathology, University of Chicago, Chicago, Illinois

Requests for reprints: Thomas F. Gajewski, University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637. Phone: 773-702-4601; Fax: 773-702-3163; E-mail: tgajewsk{at}medicine.bsd.uchicago.edu.

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.