Potential therapeutic significance of CIK cells in gefitinib resistant NSCLC with EGFR mutations

The gefitinib resistant limits its efficacy in the treatment of non-small cell lung cancer (NSCLC), thus, we tried to evaluate the drug-resistance reversal to gefitinb by the cytokine induced killer (CIK) cells. The gefitinib resistant cell line PC-9/GR was developed from a NSCLC cell line PC-9 harboring EGFR E746-A750 deletion by gefitinib selection. The effect of CIK cells alone or combination with gefitinib on PC-9/GR was determined by the cytotoxicity in vitro as well as growth inhibition of tumors in the nude mice. The immune cell subsets and cytokines expression before and after CIK cells infusion in six patients with tumors were also analyzed. An additional EGFR T790M mutation was obtained in the PC-9/GR with a resistance index of 100.16 to gefitinib. The induction of G0/G1 arrest and apoptosis and inhibition of activation of p-EGFR, p-ERK and p-AKT signaling were significantly attenuated in PC-9/GR following treated with gefitinib. Interestingly, an evident cytolytic activity was presented in the PC-9 and PC-9/GR treated with CIK cells in vitro and vivo, however, there was no significant difference in the cytolytic activity of CIK cells against PC-9 and PC-9/GR targets. In addition, a synergistic cytotoxicity was obtained by the combination CIK cells and geifitinb in PC-9/GR through the inhibition of p-ERK and p-AKT activity by CIK cells. Finally, CIK cells infusion could significantly increase the frequency and function of NK cells and decrease the frequency of Treg cells and level of TGF-β in patients with tumors. In conclusion, CIK cells have a strong cytotoxicity to PC-9/GR and a clinical immune modulation, thus it maybe a favorable treatment of NSCLC with EGFR mutations.