TRANSFECTION OF A MURINE FIBROSARCOMA WITH INTERCELLULAR-ADHESION MOLECULE-1 ENHANCES THE RESPONSE TO ADOPTIVE IMMUNOTHERAPY

Background. Increasing the ability of antitumor effector cells to leav e the vasculature and gain access to tumor cells may improve therapeut ic efficacy. We undertook this study to determine whether increased ex pression of intercellular adhesion of molecular-1 (ICAM-1) by gene tra nsfection would result in an improved response to adoptive immunothera py in vivo. Methods. C57BL/6 mice received 1 x 10(6) tumor cells on da y 0. Tumor cells examined were MCA-105 (parental), NeoR (MCA-105 trans fected with the neomycin resistance gene), or Clones 81 or 149 (MCA-10 5 cotransfected with NeoR and the gene for ICAM-1 and highly express I CAM-1). Animals were treated by use of no treatment, interleukin-2 alo ne (days 10 through 14), hyperthermia alone (days 10 and 13), or inter leukin-2 + hyperthermia, and tumor growth was reported as a ratio to s ize on day 10. In vitro cytotoxicity was assayed by using murine lymph okine-activated killer cells. Results. Tumors transfected with ICAM-1 and treated with hyperthermia + immunotherapy grew significantly (p < 0.05) slower (mean, 0.78 +/- 0.16 on day 19) than parental tumor (size , 1.35 +/- 0.22) or tumor cells transfected with NeoR alone (1.21 +/- 0.19). Tumors containing both MCA-105 and Clone 81 treated with hypert hermia + immunotherapy grew significantly slower (1.58 +/- 0.49 on day 13, p < 0.05) than untreated Clone 81 (2.38 +/- 0.46) or treated MCA- 105 (2.49 +/- 0.23) but more rapidly than treated Clone 81 (1.18 +/- 0 .08), suggesting a paracrine effect for ICAM-1. Conclusions. These fin dings show that increased expression of ICAM-1 by tumor cells results in a significant increase in antitumor efficacy of combined interleuki n-2 and hyperthermia in a murine model. Although the mechanism has yet to be elucidated, modulation of cellular adhesion may play a role in the therapeutic efficacy of cellular immunotherapy.