Lymphopenia-induced homeostatic proliferation and CD8+ T cell-mediated tumor rejection

Recent work has suggested that T cell-based immunotherapy for cancer might be more efficacious in the setting of relative lymphopenia. Although there are several potential explanations for this phenomenon, one factor may be the induction of homeostasis-driven proliferation. To examine specifically the contribution of homeostatic proliferation on CD8+ T cell-mediated tumor rejection, an adoptive transfer model was developed in which tumor-specific 2C/RAG2-/- TCR Tg CD8 + T cells were introduced into either the lymphopenic environment of RAG2-/- hosts or into P14/RAG2-/- hosts containing an irrelevant CD8+ TCR Tg population. RAG2-/- but not P14/RAG2-/- recipients supported homeostatic proliferation of transferred T cells as well as rejection of P1.HTR tumors. Despite absence of tumor rejection in P14/RAG2-/- recipients, transferred 2C cells did become activated as reflected by CFSE dilution and CD44 upregulation. However, these 2C cells showed poor IFN-gamma and IL-2 production upon restimulation, consistent with T cell anergy and similar to the hyporesponsiveness induced by administration of soluble peptide antigen.; To determine if homeostatic proliferation could uncouple T cell anergy, anergic 2C cells were transferred into RAG-/- recipients. Interestingly, transferred anergic 2C cells underwent vigorous proliferation, recovered IL-2 production, and regained the ability to reject P1.HTR tumors in RAG2-/- mice.; We then transferred polyclonal T cell populations into recipient RAG2 -/- or P14/RAG2-/- mice to extend our finds to a more clinically relevant setting. We found that depletion of CD25+ T cells was necessary for tumor rejection under these conditions and that homeostatic proliferation was critical for maintaining durable responses.; Taken together, our data suggest that homeostatic proliferation supports tumor rejection by maintaining increased numbers of functional tumor-specific CD8+ T cells. Increased numbers of T cells are activated and expand through antigen-independent proliferation, and these cells remain functional through prevention and/or reversal of T cell hyporesponsiveness.