CTLA4 Blockade Maximizes Antitumor T-Cell Activation by Dendritic Cells Presenting Idiotype Protein or Opsonized Anti-CD20 Antibody-Coated Lymphoma Cells

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Abstract
CTLA4 is a negative regulator of the costimulatory signals induced by the interaction of CD28 on T cells and B7 on dendritic cells (DCs). Antibodies (Abs) against CTLA4 can block its function and increase the activation of T cells primed to recognize antigens. The effect of CTLA4 blockade on the cross-presentation of tumor antigens by DCs to T cells was examined. Immune T cells and DC precursors were collected from patients receiving idiotype protein-pulsed DC vaccines, exposed to antigen, and examined for antitumor activity by measuring intracellular cytokine production by FACS. Idiotype-specific activation occurred in CD8+ and CD4+ T-cell populations and was up to 58 fold higher with CTLA4 blockade. These T cells could be expanded quickly and maintained tumor cytolytic activity. T-cell responses to whole tumor cell-pulsed DCs were then examined. DCs contain Fc receptors and efficiently phagocytose lymphoma cells when coated with opsonizing anti-CD20 Abs. Within a few hours, DCs ingested tumor cells and labeled proteins were observed in the cytoplasm. When anti-CD20 Ab-coated tumor-pulsed DCs were used in combination with CTLA4 blockade, up to 15 fold higher activation of Id-specific CD8+ and 3 fold higher CD4+ T cells resulted. Thus, CTLA4 blockade can enhance the measurement of Ag-specific T-cell responses and the expansion of T cells for clinical studies. In addition, the combination of CTLA4 blockade and Ab targeting of tumor to DCs is an effective method for the cross-presentation of tumor cell antigens.