Recombinant interferon‐γ can induce the expression of HLA‐DR and ‐DC on DR‐negative melanoma cells and enhance the expression of HLA‐ABC and tumor‐associated antigens

Abstract

Recombinant interferon-gamma (IFN-gamma) induced the expression of HLA-DR when added to the culture medium of HLA-DR- melanoma cell lines. In addition, IFN-gamma induced the expression of another class II antigen, HLA-DC, on a HLA-DR+ and -DC-melanoma cell line and to a lower level on a -DR- and -DC-melanoma line. IFN-gamma also enhanced the expression of HLA-ABC and beta 2-microglobulin, as well as HLA-DR on DR+ melanoma cells. In contrast, IFN-alpha gave no induction of expression of HLA-DR and DC on two DR- melanoma lines, while it did enhance the expression of HLA-ABC and of beta 2-microglobulin. The expression of 3 out of 6 melanoma-associated differentiation antigens was enhanced by IFN-gamma treatment. The modulation of antigens by IFN-gamma was both dose and time dependent. A minimum incubation time of 48 h was necessary for the appearance of HLA-DR on the two HLA-DR- melanoma lines, whereas HLA-ABC and beta 2-microglobulin were already increased after 24 h. A dose of 20 U/ml IFN-gamma started to induce the expression of HLA-DR and DC on melanoma cells GLL-19 and Me-43 and a plateau of maximum antigen expression was reached with 100 U/ml. Analyses of IFN-gamma-treated cells by flow microfluorometry showed a homogeneous distribution of increased staining intensity rather than the appearance of two cell populations. Immunoprecipitation experiments using detergent-solubilized 125I-labeled membrane proteins of IFN-gamma-treated melanoma cells and a monoclonal anti-HLA-DR antibody confirmed the presence of HLA-DR antigens. When IFN-gamma-treated cells were cultured without IFN the induced or enhanced expression of HLA antigens was reversible. Eight days after removal of IFN, the HLA-DR level was reduced by more than 90% and the level of HLA-ABC and beta 2-microglobulin by more than 50%. The demonstration of the ability of HLA-DR- melanoma cells to express HLA-DR after IFN-gamma treatment was extended to cells from other types of tumor such as gliomas, colon carcinomas and one cervical carcinoma cell line.

Exogenous expression of mouse interferon gamma cDNA in mouse neuroblastoma C1300 cells results in reduced tumorigenicity by augmented anti-tumor immunity.

“…Thus, repeated administration of anti-IFN-y antibodies should indicate more clearly the contribution of IFN-y in tumor suppression and rejection. In addition, IFN-y might induce the expression of tumorassociated antigen(s) (43,44) as well as MHC class I antigens, although the precise nature of the C1300 cell antigen is not yet known. Actually, preliminary experiments indicated that augmented CTL activity specific for the C1300 cell line was induced in the mice immunized with the high-producer cells but not in the mice bearing tumors induced by any other C1300 sublines.…”

Trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules through engagement of natural killer cells and stimulation of IFNγ secretion

“…29 Trastuzumab was recently reported to induce transcriptional inhibition of HER2 expression in HER2-overexpressing breast cancer cells by engaging Fc receptor-expressing immune effector cells to stimulate IFNg secretion in the presence of PBMC through STAT1 activation. 30 Because IFNg is a potent cytokine that stimulates HLA-ABC expression by activating STAT1 signaling, 31 we decided to examine whether the presence of immune effector cells influences any effect of trastuzumab on HLA-ABC expression. We first cultured BT474, SKBR3, SUM190, MDA-MB-361, and HCC1954 cells for 48 h in the presence or absence of trastuzumab in culture medium.…”

The treatment of established intracranial tumors by in situ retroviral IFN-γ transfer

“…[8][9][10] IFN-␥ can also enhance antigen presentation on tumor cells through increased MHC class I and II expression. [11][12][13] Furthermore, IFN-␥ has been noted to modulate tumor angiogenesis by inhibiting endothelial tube formation in vitro. 14 Recombinant IFN-␥ has been used extensively in clinical trials, 15,16 however, the high doses required to induce an antitumorigenic response resulted in severe systemic side-effects.…”