Autologous cellular immune response to primary and metastatic human melanomas and its regulation by DR antigens expressed on tumor cells

Abstract

Evidence for heterogeneity of several biological features of human malignant melanoma (Me) like morphology, cytogenetics, oncogenes activation, antigenic expression, metastatizing capacity and procoagulant activity are briefly reviewed in an attempt to distinguish findings related to primary vs. metastatic lesions. In our own studies monoclonal antibodies were used to study expression of MHC class I, class II products and of Me-associated antigens (MAA) on primary and metastatic Me cells. High expression of class I antigens was found in a high percentage of both primary and metastatic tumors, whereas DR and MAA showed a significant variation (from 3 to 90% of cells) in expression both in primary and in metastatic Me. When autologous cell-mediated immune responses were evaluated, it was found that Me cells from primary tumors but not those from lymph node metastases were able to stimulate autologous lymphocytes to proliferate and become cytotoxic for autologous Me. Clonal analysis of cytotoxic lymphocytes was then carried out in order to see whether the lack of lymphocytes reactivity to metastatic cells was due to the absence or to a low frequency of cytotoxic cells in the unstimulated PBL. CTL clones cytotoxic for autologous Me (Auto-Me) cells were indeed isolated. Three classes of CTL clones were identified: 1) one which is cytotoxic for Auto-Me; 2) a second one which lyse Auto-Me and allogeneic Me; and 3) a third one which is cytotoxic for Auto-Me and allogeneic normal and neoplastic cells. Metastatic Me cells, however, had the ability to suppress the stimulation of autologous PBL by alloantigens or IL-2. This effect was dose-dependent and was not due to absorption of IL-2 by Me cells. Since it has been reported that Me cells express class II MHC antigens, we investigated whether there was any correlation between autologous immune responses and DR expression on Me cells. Autologous lymphocytes stimulation was found to occur only with DR+ Me cells from primary lesions, whereas metastatic cells, either DR+ or DR-, did not stimulate autologous PBL. Moreover, the suppressive effect of metastatic Me cells was associated with their expression of DR antigens. The modulation of DR antigens on Me cells by Interferon-gamma correlated positively with their suppressive capacity. Thus, it appears that primary Me can behave differently from the metastatic one in their interactions with the immune system of autologous host. These findings suggest that DR antigens on Me cells may have an important role in the regulation of autologous immune responses.

Activation of lymphocyte anti-tumour responses in man: Effector heterogeneity and the search for immunomodulators

“…The frequency of response in patients with metastasis is lower than in those with more confined disease [8,9]. However, the finding of response to some secondary tumours contrasts sharply with findings in the melanoma system where reaction was apparently confined to the primary turnout [10] and cells from secondary deposits seemed incapable of stimulation of patients' lymphocytes.…”

Interferon-mediated enhancement of metastasis. Are MHC antigens involved?

“…The involvement of a T cell-mediated response, which can be either stimulated or suppressed by different MHC antigens, has been demonstrated in other studies on metastasis: for example, HLA-DR positive human metastatic melanoma cells, which are able to suppress the IL-2-dependent generation of autologous cytotoxic lymphocytes, augment both DR expression and suppressive activity after IFNgamma treatment [19].…”

Susceptibility of human and murine drug-resistant tumor cells to the lytic activity of rIL2 - activated lymphocytes (LAK)

“…This phenomenon is amplified by the presence of different neoplastic localizations which can behave differently in the same patient (i.e., the primary tumor and the metastastic one; two, or more metastases) [3]. This feature may explain the frequent emergence of drug-resistant neoplastic cells, even after a good initial response to chemotherapy [2].…”