Autocrine costimulation: tumor-specific CD28-mediated costimulation of T cells by in situ production of a bifunctional B7-anti-CEA diabody fusion protein.
T cells require two distinct signals for optimal activation, an antigen-specific signal, provided by engagement of the T-cell receptor (TCR) and a second costimulatory signal mediated by engagement of CD28 with members of the B7 family. Although infiltrating T cells are present in many malignancies, they appear to be mostly anergic and do not attack the tumor, presumably because of the absence of activation and/or costimulatory signals. Here we describe a novel strategy for the in situ activation of tumor-specific T cells. We genetically modified T cells to secrete a bifunctional fusion protein, comprising the extracellular portion of B7-1 fused to an anticarcinoembryonic antigen (CEA) diabody. In coculture with CEA(+) tumor cells autocrine and paracrine secretion of B7-alphaCEA provided a potent tumor-specific costimulatory signal to T cells in combination with a recombinant alphaCEAxalphaCD3 bispecific diabody. B7-alphaCEA was also found to strongly enhance survival and tumor-specific activation of T cells expressing an anti-CEA TCRzeta-based chimeric immune receptor (CIR) both when expressed in cis by the T cells themselves as well as in trans, when added to the culture medium. In the absence of costimulatory signals provided by the tumor, our strategy allows T cells to "arm themselves" by the production of tumor-specific costimulatory proteins. Sustained in situ production of such molecules, like the B7-diabody fusion protein may create a favorable local environment for the activation and proliferation of tumor-reactive T cells and increase the tumoricidal activity of immunotherapeutic approaches targeting the TCR pathway.
Blanco
Belén
B
Department of Immunology, Hospital Universitario Clínica Puerta de Hierro, Madrid, Spain.
Holliger
Philipp
P
Alvarez-Vallina
Luis
L
D019898:Autocrine Communication / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D003110:Colonic Neoplasms / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015316:Genetic Therapy; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000276:immunology* / Q000502:physiology
D018122:B7-1 Antigen; D018106:CD28 Antigens; D002272:Carcinoembryonic Antigen; D017931:DNA Primers; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins