Date

October 2012

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Molecular Microbiology and Immunology

Institution

Oregon Health & Science University

Abstract

The role of CD4 T cells in cancer immunotherapy has been debated due to the multifaceted and diverse functions of CD4 T cell lineages. Pathogen-derived models have shown that CD4 T cells have an important role in helping to prime and maintain effective long-term immunity. However, there are multiple types of CD4 T cells such as Foxp3+ CD4 T cells called regulatory T cells (Tregs), which have an important role in resolving immune activation during infection and suppressing the immune response to self-antigens. Since tumor-associated antigens are often overexpressed or mutated self-antigens, Tregs are known to reduce anti-tumor immune responses. Chapter 2 will discuss the advantages of tumor-specific CD4 T cells during adoptive immunotherapy of melanoma in a lymphopenic model. We observed superior therapeutic efficacy of adoptive immunotherapy with tumor-specific CD4 and CD8 T cells in tumor-bearing RAG-deficient lymphopenic mice compared to treatment with CD8 T cells alone. Mice treated with CD4 and CD8 T cells had an increased number of tumor-reactive CD8 T cells and removal of CD4 cells early after adoptive immunotherapy reduced therapeutic efficacy and increased expression of the exhaustion marker PD-1 on CD8 T cells. Tumor-specific CD4 T cells were able to maintain effector phenotype cells and reduced the expression of the apoptosis inducing factor TRAIL on CD8 T cells. Together our findings indicate the advantage of using tumor-specific CD4 T cells in adoptive immunotherapy trials for cancer. Chapter 3 will describe the elimination of Tregs in a multiple vaccination model, where anti-tumor immunity is induced in the same challenged or tumor-bearing mice (active-specific). Previously our group showed three vaccinations with a whole-tumor vaccine transduced to secrete GM-CSF produced fewer therapeutic T cells than a single vaccination. This loss in efficacy correlated with increased Tregs numbers. Our previous report used a model of T cell adoptive immunotherapy with splenocytes from vaccinated animals. It is possible that this model did not account for migration of tumor-specific T cells to resident tissues. Here we show that during active-specific immunotherapy partial depletion of CD4 T cells skewed homeostatic proliferation toward a non-Treg phenotype and enhanced protection to a large dose tumor challenge (20x TD[subscript 100]) compared to non-depleted mice. We also examined whether route of vaccination altered Treg numbers or ability to protect against tumor challenge and found there was no difference in protection, using three different vaccination administration methods. Together these studies indicate the importance of CD4 T cells during priming and maintenance of anti-tumor responses. However, these studies also exemplify the paradox that CD4 T cells can be both positive and detrimental for anti-tumor immunity.

Identifier

doi:10.6083/M49Z92XM

School

School of Medicine

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