Biological a and iimmunological a aspects o of m malignant mesothelioma

Malignant mesothelioma (MM) is an aggressive tumour, which is strongly associated with previous asbestos exposure and is resistant to all conven- tional anticancer therapies. An understanding of the biological properties of MM may provide insights into useful therapeutic strategies, and MM cell lines and ani- mal models have been major contributors to our current knowledge of this tumour. Although karyotypic abnormalities 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 cur- rently identified tumour suppressor genes. A number of growth factors, including platelet derived growth factors A and B (PDGF-A and -B), insulin-like growth fac- tor I and transforming growth factor-beta (TGF-β), 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 stimulant for MM or to modify immune responses to the tumour. Some data support an autocrine role for PDGF-A. MM cell lines are susceptible to lysis by a variety of immune effector cells, and their growth can often be inhibited by cytokines. The possibility of stimulating an immune response to MM by genetic manipulation of the tumour cells has been investigated using a murine model. The data so far suggest that transfection of allogeneic class I major histocompatibility complex genes or syngeneic class II genes alone is unlikely to induce protective immunity. Expression of the co-stimulatory molecule B7-1 stimulated tumour-specific cytotoxic T-lymphocytes (CTL), and gen- eration of these CTL was associated with delayed tumour development or tumour rejection. Furthermore, some, but not all, B7-1 expressing clones from one murine cell line were able to generate an antitumour response, which conferred resistance to the parental tumour. However, these experiments also illustrated the hetero- geneity of immunogenicity which exists both within and between MM tumours. It is likely that genetic modification using the genes for more than one immunologi- cally relevant molecule will be necessary for successful induction of immunity to the least immunogenic examples of this tumour.