CTLA4 blockade maximizes antitumor T-cell activation by dendritic cells presenting idiotype protein or opsonized anti-CD20 antibody-coated lymphoma cells.
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.
Hsu
Frank J
FJ
Section of Oncology, Yale University, WWW213, 333 Cedar Street, New Haven, CT 06520, USA. Frank.Hsu@yale.edu
Komarovskaya
Marina
M
D000069594:Abatacept; D017951:Antigen Presentation; D015703:Antigens, CD; D018951:Antigens, CD20 / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates; D007130:Immunoglobulin Idiotypes / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008224:Lymphoma, Follicular / Q000737:chemistry / Q000276:immunology* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000276:immunology*; D009895:Opsonin Proteins / Q000276:immunology*; D010587:Phagocytosis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D018951:Antigens, CD20; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D016207:Cytokines; D018796:Immunoconjugates; D007130:Immunoglobulin Idiotypes; D009895:Opsonin Proteins; D000069594:Abatacept