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


METHODS
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
Justin
J
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Brown
Ian E
IE
Zha
Yuan-Yuan
YY
Blank
Christian
C
Strickler
John
J
Wouters
Harald
H
Zhang
Long
L
Gajewski
Thomas F
TF
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017635:Clonal Anergy; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*