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 leave the vasculature and gain access to tumor cells may improve therapeutic efficacy. We undertook this study to determine whether increased expression of intercellular adhesion of molecular-1 (ICAM-1) by gene transfection would result in an improved response to adoptive immunotherapy in vivo. Methods. C57BL/6 mice received 1 x 10(6) tumor cells on day 0. Tumor cells examined were MCA-105 (parental), NeoR (MCA-105 transfected with the neomycin resistance gene), or Clones 81 or 149 (MCA-105 cotransfected with NeoR and the gene for ICAM-1 and highly express ICAM-1). Animals were treated by use of no treatment, interleukin-2 alone (days 10 through 14), hyperthermia alone (days 10 and 13), or interleukin-2 + hyperthermia, and tumor growth was reported as a ratio to size on day 10. In vitro cytotoxicity was assayed by using murine lymphokine-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 hyperthermia + 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 findings show that increased expression of ICAM-1 by tumor cells results in a significant increase in antitumor efficacy of combined interleukin-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.