BIOLOGICAL AND IMMUNOLOGICAL ASPECTS OF MALIGNANT MESOTHELIOMA

Malignant mesothelioma (MM) is an aggressive tumour, which is strongly associated with previous asbestos exposure and is resistant to all co nventional anticancer therapies. An understanding of the biological pr operties of MM may provide insights into useful therapeutic strategies , and MM cell lines and animal models have been major contributors to our current knowledge of this tumour. Although karyotypic abnormalitie s are frequent, there is no clear evidence of a mesothelioma-specific chromosomal aberration. Similarly, there is no evidence of activation or over-expression of a known oncogene, or of the inactivation of curr ently identified tumour suppressor genes, A number of growth factors, including platelet derived growth factors A and B (PDGF-A and -B), ins ulin-like growth factor I and transforming growth factor-beta (TGF-bet a), and some of their receptors, have been reported to be expressed by MM cells, and each has the potential to play a role as a growth stimu lant for MM or to modify immune responses to the tumour, Some data sup port an autocrine role for PDGF-A. MM cell lines are susceptible to ly sis by a variety of immune effector cells, and their growth can often be inhibited by cytokines. The possibility of stimulating an immune re sponse to MM by genetic manipulation of the tumour cells has been inve stigated using a murine model. The data so far suggest that transfecti on of allogeneic class I major histocompatibility complex genes or syn geneic class II genes alone is unlikely to induce protective immunity, Expression of the co-stimulatory molecule B7-1 stimulated tumour-spec ific cytotoxic T-lymphocytes (CTL), and generation of these CTL was as sociated with delayed tumour development or tumour rejection. Furtherm ore, some, but not all, B7-1 expressing clones from one murine cell li ne were able to generate an antitumour response, which conferred resis tance to the parental tumour. However, these experiments also illustra ted the heterogeneity of immunogenicity which exists both within and b etween MM tumours, It is likely that genetic modification using the ge nes for more than one immunologically relevant molecule will be necess ary for successful induction of immunity to the least immunogenic exam ples of this tumour.