178 Altered Mechanisms of Apoptosis in Colon Cancer: Fas Resistance and Counterattack in the Tumor-Immune Conflict JOE O’CONNELL, a MICHAEL W. BENNETT, KENNETH NALLY, AILEEN HOUSTON, GERALD C. O’SULLIVAN, AND FERGUS SHANAHAN Department of Medicine, National University of Ireland, Cork, Ireland ABSTRACT: Fas (CD95/APO-1) is a cell surface “death receptor” that mediates apoptosis upon engagement by its ligand, FasL. Fas-mediated apoptosis of lym- phocytes normally serves immunoregulatory roles, including tolerance acqui- sition, immune response termination, and maintenance of immune privilege in certain organs. Colon tumors can exploit this lymphocyte death program by expressing FasL. This may enable colon tumors to mount a “Fas counterat- tack” against antitumor lymphocytes, impairing antitumor immune responses. FasL-expressing colon tumor–derived cell lines can trigger Fas-mediated apo- ptosis of cocultured T cells in vitro. FasL expressed in esophageal cancer has been significantly associated with apoptosis and depletion of tumor-infiltrating lymphocytes (TIL) in vivo. FasL may also facilitate metastatic colonization of Fas-sensitive organs such as the liver, by inducing apoptosis of target organ cells. Normal colonic epithelial cells express Fas and are relatively sensitive to Fas-mediated apoptosis. By contrast, colon tumor–derived cell lines are usually resistant to induction of Fas-mediated apoptosis, and colon cancer cells fre- quently coexpress Fas and FasL. The mechanisms allowing resistance to Fas- mediated apoptosis are complex, and defects have been identified at several levels of Fas signal transduction. The “Bcl-2 rheostat” may be pitched against apoptosis in colon cancer, inasmuch as overexpression of Bcl-2, downregulation of Bak, and mutation of Bax are common defects in colon tumors. Caspase-1 is also downregulated in colon cancer. The high frequency of p53 mutations in late-stage cancers may also inhibit Fas signaling. Fundamental defects in apo- ptosis signaling may contribute to both immuno- and chemoresistance in colon cancer and allow expression of FasL to counterattack antitumor lymphocytes. INTRODUCTION Fas (CD95/APO-1) is a cell surface “death receptor” of the tumor necrosis factor (TNF) receptor family. Triggering of Fas by its ligand, FasL, causes programmed cell death or apoptosis of Fas-expressing cells, provided that the cells are sensitive to the Fas death signal. Lymphocytes upregulate cell surface Fas and FasL upon ac- tivation, and Fas-mediated apoptosis is involved in important regulatory processes in the immune system. FasL helps to delete autoreactive lymphocytes during tolerance acquisition and activated T and B cells during the termination of immune responses. a Address for correspondence: Dr. Joe O’Connell, Department of Medicine, Clinical Sciences Building, University Hospital, Cork, Ireland. Voice: 00353 21 901231; fax: 00353 21 345300. j.oconnell@ucc.ie.