PHENOTYPIC AND FUNCTIONAL-ANALYSIS OF FAS (CD95) EXPRESSION IN PRIMARY CENTRAL-NERVOUS-SYSTEM LYMPHOMA OF PATIENTS WITH ACQUIRED-IMMUNODEFICIENCY-SYNDROME

The poor prognosis associated with patients afflicted with the acquire d immunodeficiency syndrome and primary central nervous system lymphom a (AIDS-PCNSL) is due in part to the intrinsic resistance of this Epst ein-Barr virus (EBV)-associated tumor to conventional antineoplastic t herapy. Fas (CD95) is a transmembrane protein receptor that transmits an intracellular signal leading to rapid programmed cell death followi ng ligation with its natural ligand or anti-Fas antibodies. Fas expres sion and function were assessed in AIDS-PCNSL biopsy samples and in EB V+ human B-cell tumors that spontaneously developed in severe combined immune deficient (SCID) mice engrafted with human lymphocytes (hu-PBL -SCID mice). All tumors samples showed high-density surface expression of Fas by flow cytometry or immunohistochemical staining. Cells from two AIDS-PCNSL biopsy samples that did not express pan B-cell markers did not express Fas antigen. All tumors examined were susceptible to F as-mediated apoptosis, as measured by standard assays for endonucleoly tic cleavage of DNA, The response to Fas-mediated apoptosis was depend ent on log-fold increases in the concentration of immobilized anti-fas antibody, but could also be induced with a mobilized anti-fas antibod y. No evidence for intrinsic resistance to Fas-mediated apoptosis tie, secreted or truncated forms of Fas) could he shown. Radiation-induced apoptosis of neoplastic EBV+ B cells was enhanced by activation of Fa s, and prolonged exposure to interleukin-2 increased both Fas expressi on and Fas-induced apoptosis. As the normal brain parenchyma appears t o have either low-density or absent expression of Fas, and antineoplas tic systemic toxicity, local delivery of Fas-activating molecules coul d prove to be a useful component in the multimodal treatment of AIDS-P CNSL. (C) 1997 by The American Society of Hematology.