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Deleterious Changes To The T Cell Compartment Following Immunotherapy
AuthorAlderson, Kory Lane
AdvisorMurphy, William J
Biochemistry and Molecular Biology
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Abstract: The combination of anti-CD40 and interleukin-2 is a potent immunotherapy regimen that results in synergistic anti-tumor responses. This has been demonstrated in multiple murine tumor models of metastatic disease with various tumor types. The primary anti-tumor responses elicited by this combination are capable of inducing tumor regression and prolonged survival. However, the generation of secondary T cell responses after irradiated tumor vaccine is abrogated after anti-CD40 and IL-2. This abrogation also occurs after other immunotherapeutic approaches that prompt the production of large amounts of interferon-gamma (IFNγ). These observations correlated with a significant skewing of the T cell compartment. First, we observed a selective decreased of conventional CD4+ T cells following immunotherapy. Second, we observed a more than five fold expansion of memory phenotype cells which were incapable of generating responses to new antigens. The data presented here suggest that despite initial tumor regression, potent systemic immunotherapy may impair responses to new immunological challenges.Selective CD4+ T cell death after immunotherapy results in an alteration in the ratio of CD4+ T cells to CD8+ T cells and impairs the generation of a secondary immune response. Our data suggest that this phenomenon after immunotherapy is the result of the selective upregulation of programmed death-1 (PD-1) and its IFNγ responsive ligand, B7-H1. We show that the expression of PD-1 is restricted to the surface of Foxp3neg CD4+ T cells and that CD8+ T cells and CD4+ Foxp3+ regulatory T cells remain PD-1 low after immunotherapy. Furthermore, the expression of PD-1 correlates with CD4+ T cell death after immunotherapy. In the absence of IFNγ either by the use of mice lacking IFNγ (IFNγ-/-) or the receptor for IFNγ (IFNγR-/-), B7-H1 remains low after immunotherapy. Subsequently, CD4+ T cells expand in response to immunotherapy in the absence of IFNγ responsive B7-H1. We observed a significant expansion of memory phenotype T cells after cytokine based immunotherapy which correlated with impairment of proliferative responses to new antigens. Memory T cells are more sensitive to cytokine stimulation than naïve T cells. Therefore, we used a young thymectomized mouse model to determine if pre-existing memory T cells were preferentially expanded by immunotherapy. The thymectomized mouse model allowed us to evaluate long term T cell responses to immunotherapy in the absence of de novo T cell generation. Using this model, we observed expansion of memory T cells, within both the CD4+ and CD8+ T cell compartments without a major sacrifice of the size of the naïve T cell compartment. Compared to memory T cell expansion, there was relatively small change in the naïve T cell compartment. Naïve CD8+ T cell numbers were unchanged by immunotherapy and naïve CD4+ T cells were decreased by less than half. Memory T cells were still significantly expanded after 30 days of rest. Furthermore, the persistent expansion of memory T cells correlated with a maintained decrease in proliferative function to new antigens. Taken together, these data demonstrate a long term consequence of immunotherapy to the phenotypic makeup and, importantly, the function of the T cell compartment.