Cytokines which (i) augment major histocompatibility (MHC) and/or tumor antigen expression on the tumor cell surface and/or (ii) play a role in the development of an antitumor T-cell response may play a pivotal role by enhancing tumor recognition/killing by the humoral and/or cellular components of the immune system. Experimental studies and clinical trials established that interferon (IFN) administration increased the expression of tumor-associated antigens on the surface of human carcinoma cells. For example, IFN-omega, a newly described interferon species, can upregulate HLA class I, CEA, ICAM-1 and episialin (DF3/MUC1), but not HLA class II, expression on the surface of human carcinoma cells. However, a combination of IFN-omega with IFN-gamma synergistically increased of CEA, HLA class I and ICAM-1 expression, indicating that IFN-omega functions as a Type I interferon. Several studies have shown that combining interferon-based tumor antigen upregulation with molecularly designed monoclonal antibodies (MAb) (ie., 125-I-CC49 sFv for scintigraphy or 131-I-CC49 for immunotherapy) can significantly improve tumor detection and/or therapy when compared with MAb alone. Other cytokines, particularly, interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF) play instrumental roles in the development of antitumor cell-mediated immune responses. In recent studies, the addition of low-dose IL-2 with immunization utilizing a recombinant vaccinia-CEA viral construct (rV-CEA) significantly enhanced the regression of and protection from challenge with CEA-expressing tumors. T-cell assays revealed that IL-2 treatment significantly increased CEA-specific T-cell proliferative and cytotoxic responses. When GM-CSF was co-administered as a recombinant vaccinia viral construct (rV-GM-CSF) with rV-CEA or by infecting poorly immunogenic tumor cells with rV-GM-CSF, primary tumor growth was suppressed. Furthermore, those tumor-free, immunized mice were protected from subsequent tumor challenge. Gamma-irradiation or in vivo T-cell depletion of the recipient mice abrogated both the antitumor and protective effects of the immunization schema including GM-CSF. The results indicate that intervention with selected cytokines can significantly enhance the efficacy of humoral (ie., MAbs) and cell-mediated (cytotoxic T-cell) approaches to tumor treatment.
