A promising strategy for
cancer treatment is adoptive gene therapy/
immunotherapy by genetically modifying T cells with a
chimeric T cell receptor (cTCR). When transduced T cells (T-bodies) specifically bind to
tumor antigens through cTCR, they will become cytotoxic T lymphocytes (CTL) and lyse the
tumor cells in a non-major histocompatibility complex (MHC)-restricted manner. Both the FcR gamma-chain and the
TCR zeta-chain have been used to construct such cTCR, and both have shown specific cytolytic functions against
tumor cells. However, most researchers believe that the zeta-chain generates stronger cytolytic activities against
tumor than the gamma-chain and therefore would be a better candidate for cTCR construction. On the other hand, because of the lack of costimulation signaling in such constructs, the T-body might cause activation-induced T cell death (AICD) when bound to
tumor antigens. Therefore, one can argue that the gamma-chain might generate less AICD than the zeta-chain because the gamma-chain has only one immunoreceptor tyrosine-based activation motif (ITAM), and the cytolytic activities can be therefore recycled. Two cTCR, GAHgamma and GAHzeta, were constructed and evaluated for
cytokine production, specific cytolytic function and AICD in T-bodies after exposure to
tumor cells. Using EGP-2-positive LS174T
colorectal carcinoma cells as targets, there was no substantial difference observed between a gamma-chain or zeta-chain as the T-body signaling moiety in terms of specific cytolytic functions and induced
cytokine production. This paper also demonstrates that, in the absence of a costimulation system,
tumor antigen may not trigger apoptosis of T cells transduced with a cTCR carrying either an FcR gamma-chain or a
TCR zeta-chain. These observations challenge current ideas about the role of ITAM in T cell activation.