Abstract
BackgroundWe have previously demonstrated that temporary depletion of CD4 T cells in mice with progressive B16 melanoma, followed by surgical tumor excision, induces protective memory CD8 T cell responses to melanoma/melanocyte antigens. We also showed that persistence of these CD8 T cells is supported, in an antigen-dependent fashion, by concurrent autoimmune melanocyte destruction. Herein we explore the requirement of CD4 T cell help in priming and maintaining this protective CD8 T cell response to melanoma.Methodology and Principal FindingsTo induce melanoma/melanocyte antigen-specific CD8 T cells, B16 tumor bearing mice were depleted of regulatory T cells (Treg) by either temporary, or long-term continuous treatment with anti-CD4 (mAb clone GK1.5). Total depletion of CD4 T cells led to significant priming of IFN-γ-producing CD8 T cell responses to TRP-2 and gp100. Surprisingly, treatment with anti-CD25 (mAb clone PC61), to specifically deplete Treg cells while leaving help intact, was ineffective at priming CD8 T cells. Thirty to sixty days after primary tumors were surgically excised, mice completely lacking CD4 T cell help developed autoimmune vitiligo, and maintained antigen-specific memory CD8 T cell responses that were highly effective at producing cytokines (IFN-γ, TNF-α, and IL-2). Mice lacking total CD4 T cell help also mounted protection against re-challenge with B16 melanoma sixty days after primary tumor excision.Conclusions and SignificanceThis work establishes that CD4 T cell help is dispensable for the generation of protective memory T cell responses to melanoma. Our findings support further use of CD4 T cell depletion therapy for inducing long-lived immunity to cancer.
Highlights
A major goal of tumor immunotherapy has been the generation of long-lived, protective CD8 T cell memory
This work establishes that CD4 T cell help is dispensable for the generation of protective memory T cell responses to melanoma
Our previous work has demonstrated that temporary depletion of CD4+CD25+ regulatory T cells (Treg) in melanoma tumor-bearing mice drives the priming of melanoma/ melanocyte antigen-specific CD8 T cells that develop into protective memory following curative excision of the primary tumor [2,3]
Summary
A major goal of tumor immunotherapy has been the generation of long-lived, protective CD8 T cell memory. We more recently showed that these CD8 T cells are maintained in a functional state, as long as 600 days following priming, by melanocyte antigen provided in the context of autoimmune vitiligo [4]. They represent a non-classical type of antigen-dependent T cell memory [4]. In these studies, regulatory T cells were depleted using an antibody to CD4 (mAb clone GK1.5). We explore the requirement of CD4 T cell help in priming and maintaining this protective CD8 T cell response to melanoma
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