CD8(+) CTL play important roles against
malignancy in both active and passive immunotherapy. Nonetheless, the success of antitumor CTL responses may be improved by additional therapeutic modalities.
Radiotherapy, which has a long-standing use in treating neoplastic disease, has been found to induce unique biologic alterations in
cancer cells affecting Fas gene expression, which, consequently, may influence the overall lytic efficiency of CTL. Here, in a mouse
adenocarcinoma cell model, we examined whether exposure of these
tumor cells to sublethal doses of irradiation 1) enhances Fas expression, leading to more efficient CTL killing via Fas-dependent mechanisms in vitro; and 2) improves antitumor activity in vivo by adoptive transfer of these Ag-specific CTL. Treatment of carcinoembryonic Ag-expressing MC38
adenocarcinoma cells with irradiation (20 Gy) in vitro enhanced Fas expression at molecular, phenotypic, and functional levels. Furthermore, irradiation sensitized these targets to Ag-specific CTL killing via the Fas/
Fas ligand pathway. We examined the effect of localized irradiation of s.c. growing
tumors on the efficiency of CTL adoptive immunotherapy. Irradiation caused up-regulation of Fas by these
tumor cells in situ, based on immunohistochemistry. Moreover, localized irradiation of the
tumor significantly potentiated
tumor rejection by these carcinoembryonic Ag-specific CTL. Overall, these results showed for the first time that 1) regulation of the Fas pathway in
tumor cells by irradiation plays an important role in their sensitization to Ag-specific CTL; and 2) a combination regimen of
tumor-targeted irradiation and CTL promotes more effective antitumor responses in vivo, which may have implications for the combination of
immunotherapy and
radiation therapy.