Biologic response modifiers in acute lymphoblastic leukemia.
Despite the presence of tumor antigens, the paucity of clinically significant T-cell mediated immune responses against human tumors is striking. This may, in part, be because of the inability of cancer cells to function as efficient antigen-presenting cells. For full activation, T cells must receive two signals delivered by antigen-presenting cells. The first is antigen-specific and is delivered by presentation of antigenic peptide by the major histocompatibility complex molecules to the T-cell receptor. This signal, although necessary, is in itself insufficient to mediate T-cell activation, cytokine release, and subsequent T-cell proliferation and function. For full T-cell activation, T cells require delivery of a secondary, costimulatory signal, such as that delivered by members of the B7 family to their receptor on the T-cell, CD28. Delivery of an antigen signal in the absence of costimulation does not result in productive immunity, but rather in anergy, a state of antigen-specific T-cell nonresponsiveness. To induce T-cell proliferation against B-cell malignancies, the tumor cell must first be induced to express B7 or the tumor antigen must be presented by an efficient antigen-presenting cell. Simple expression of B7 on the tumor cell alone, however, cannot reverse anergy. Reversal of anergy is a complex process involving stepwise repair of the T-cell defect and can be accomplished by prolonged exposure to interleukin-2, signaling through the CD2 pathway, followed by antigen presentation with B7-mediated costimulation. Successful immunotherapeutic strategies in the B-cell malignancies will likely require steps to reverse established anergy in the tumor-bearing host as well as effective tumor-antigen presentation.
Gribben
J G
JG
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Cardoso
A A
AA
Schultze
J L
JL
Nadler
L M
LM
D002051:Burkitt Lymphoma / Q000628:therapy; D018106:CD28 Antigens / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007155:Immunologic Factors / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D018106:CD28 Antigens; D007155:Immunologic Factors; D007376:Interleukin-2