CD8(+) tumor-infiltrating lymphocytes are primed for Fas-mediated activation-induced cell death but are not apoptotic in situ

Induction of Fas-mediated activation-induced cell death in antitumor T cell s has been hypothesized to permit tumor escape from immune destruction. Sev eral laboratories have proposed that expression of Fas ligand (L) by tumor is the basis for this form of T cell tolerance. In this study, we character ized murine tumor-infiltrating lymphocytes (TIL) for activation status, cel l cycle status, level of apoptosis, cytokine secretion, and proliferative c apacity. TILs express multiple activation markers (circa CD69, CD95L, CD122 , and LFA-1) and contain IL-2 and IFN-gamma mRNAs, but are neither cycling nor apoptotic in situ. In addition, TIL are dramatically suppressed in prol iferative response and do not secrete IL-2 and IFN-gamma. However, upon pur ification and activation in vitro, TIL secrete high levels of IL-2 and IFN- gamma, enter S phase, and then die by Fas-mediated apoptosis. Activation by injection of anti-TCR Ab or IL-2 into tumor-bearing mice induced TIL entra nce into S phase preceding apoptosis, showing that TIL have functional TCR- mediated signal transduction in situ. Our data demonstrate that TIL, not tu mor, express both Fas and FasL, are arrested in G(1), do not secrete cytoki ne in situ, and, upon activation in vitro and in vivo, rapidly die by activ ation-induced cell death.