Study of the Susceptibility of Antitumor Drug-Resistant Cells to LAK Cells

Abstract

It has been hypothesized that lymphokine-activated killer (LAK) cells may be effective against antitumor drug resistant (ATDR) squamous cell carcinoma. The objective of this study was to determine 1) the susceptibility of ATDR human tumor cell lines to interleukin-2 (IL-2)-induced LAK cell-mediated cytotoxicity, and to assess 2) the characteristics of the population of LAK cells as effector cells on the tumor cell lines tested and 3) the relationship between the susceptibility of ATDR cells and their expression of surface antigens.Parent strains of CEM (derived from leukemia), KB (derived from oral squamous cell carcinoma), and TCM (derived from metastasized lung cell carcinoma from oral squamous cell carcinoma) cells were used as drug-sensitive cells. The ATDR cell lines were established from the parent cells used; the ATDR cell lines were CEM (resistant to vinblastine, VLB; CEM/VLB0.1 and CEM/VLB1.0), KB (resistant to cisplatin, CDDP, and bleomycin, BLM; KB/CDDP1.0 and KB/BLM1.0, respectively) and TCM (resistant to CDDP; TCM/CDDP1.0). Peripheral blood lymphocytes were obtained from nine healthy volunteers and fractionated; the fractions consisted of unfractionated whole cells, CD 4 + cells, CD 8 + cells, and CD16+ cells. Each fraction was cultured with IL-2, and the induced LAK cells were used as effector cells.Whole-LAK cells were the most cytotoxic against all ATDR cell lines tested (as compared with the parent cells). However, the antitumor activity of the fractionated cells was limited (antitumor activity: CD16+-LAK, 60-80% on CEM/VLB0.1 and 1.0; CD 8+-LAK, about 30% on KB/CDDP1.0 and about 50% on TCM/CDDP1.0). The expressions of P-glycoprotein (Pgp), major histocompatibility complex (MHC) class I, intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function-associated antigen-3 (LFA-3) were respectively high in CEM/VLB; KB/CDDP1.0, KB/BLM1.0 and TCM/CDDP1.0; KB/CDDP1.0 and KB/BLM1.0; and TCM/CDDP1.0. In contrast, the susceptibility of the ATDR cells to LAK killing was not affected by anti-P-gp, anti-MHC class I, anti-ICAM-1, or anti-LFA-3 monoclonal antibodies.These results indicate that the effective population of LAK cells varies according to the tumor cell line, and are consistent with the assumption that the susceptibility of drug resistant cells to LAK cells depends on the property of the parent tumor cells and the type of antitumor drug that induces ATDR cells.