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

Abstract

Data continues to accumulate on the immunological reaction against solid human cancers. The evidence at the present time supports the view that rather than being immunologically invisible, tumour cell antigens are recognised by at least three lymphocyte subsets. Helper T cells can be induced to proliferate upon exposure to cells of the autologous tumour and to secrete detectable levels of interleukin 2 (IL-2). Cultured T cell lines and clones can be shown to respond in primed lymphocyte tests not only to autologous tumour cells but also to allogeneic tumour cells of the same histology and anatomic location. Cytotoxic T cells manifest specific reactivity against cells of the autologous tumour which is distinguishable from natural killing (NK) on the basis of specificity and organ distribution. Natural killer cells can lyse freshly isolated autologous tumour cells after purification on Percoll gradients or when activated by IL-2. There is thus a demonstrable heterogeneity of response to human cancer in unseparated lymphocyte populations and at the clonal level. In limiting dilution assays lymphocytes at the tumour site respond more frequently to autologous tumour relative to NK targets. For at least some tumours there is evidence that the expression of auto-tumour reactivity but not NK correlates with the clinical course of the disease and is a favourable prognostic indicator. The finding of these auto-tumour reactivities has important implications for the search for immunomodulating drugs for cancer treatment. However, it must be recognised that the response is heterogeneous and that the immune system comprises multiple interactive elements that exhibit both positive and negative control. Any treatment modality must take this into account and seek to focus on specific activation of the tumour lytic populations or the inhibition of negative regulatory elements as opposed to seeking a more general augmentation of immune reactivity which may, by stimulating suppressor cells, have a counterproductive effect.

Proliferative and/or cytotoxic activity of lymphocyte clones to autologous human melanoma

“…In cancer patients, the presence of helper T cells which can be stimulated to proliferate by Auto-Tu has been inferred from the results of positive in vitro autologous MLTC (Vhnky and Klein, 1982;Vose and Bonnard, 1982;Vose, 1987). More direct evidence for these Auto-Tu proliferating T cells has been derived from the isolation of T lymphocyte clones with features of T helper lymphocytes (Vose and White, 1983;Roberts et al, 1986;Mukherji et al, 1987).…”

“…1987). This reaction, which is suggestive of an antigenic recognition process by immune T cells, is found more frequently with tumor cells isolated from primary than from metastatic lesions (Vanky et al, 1983;Fossati et al, 1984;Guerry et al, 1984;Vose, 1987). Lymphocytes from tumor-invaded lymph nodes fail to proliferate in the presence of autologous metastatic carcinoma cells (Cozzolino et a l .…”

“…However, after removal of lymphocytes with suppressor activity, reactivity to Auto-Tu is restored, but only when IL-2 is added (Cozzolino et al, 1987). Lymphocyte clones with proliferative activity for Auto-Tu, however, have been described in some cases (Vose andWhite, 1983: Roberts et al, 1986;Mukherji et al, 1987).…”

In search of specific cytotoxic T lymphocytes infiltrating or accompanying human ovarian carcinoma

“…In fact, the majority of clinical remissions have been observed in two human tumours for which there is reason to suspect substantial immunogenicity: melanoma and renal carcinoma (see for review [5,32]). …”

Lack of suppressive activity of human primary melanoma cells on the activation of autologous lymphocytes

“…The immune response of lymphocytes from cancer patients to autologous tumors, mainly to localized neoplasms, has been evidenced by the extensive studies of Vose et al [24] and Vanky et al [23] for a variety of histologically different tumors. Therefore, from this collective data it can tentatively be concluded that primary but not metastatic tumors may express tumorassociated antigens against which the patient can mount an immune response; in addition metastatic invasion and progression may be implemented by the ability acquired by these tumor cells to suppress the immune attack of the host.…”