Smith, Mark Ernest Fitzgerald; (1990) Immunoregulatory molecules in tumours. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes the expression of immunoregulatory molecules (LFA-3, ICAM-1, HLA-A,B,C and HLA-D antigens) in normal tissues and carcinomas. The expression of tumour immunoregulatory molecules was considered abnormal when it differed from that of the corresponding normal epithelium. To aid a rational interpretation of tumour LFA-3 and ICAM-1 expression, the constitutive expression of these molecules in normal tissues was studied. The abnormal tumour phenotypes identified in colorectal carcinomas and derived cell lines included weak expression of all HLA-A,B,C antigens, complete loss of all HLA-A,B,C antigens, the selective loss of individual HLA-A,B,C allele products, the lack of inducibility of HLA-D antigens and the loss of LFA-3. Some of these abnormalities were also detected in breast and urinary bladder carcinomas, though their frequencies varied greatly between different tumour types. The selective loss of an HLA-A1 antigen from the colorectal carcinoma cell line HCA-7 was associated with the retention of the HLA-A1 and HLA-DQA genes. Mutated p53 and ras oncogene products, which occur commonly in carcinomas, are potential targets of T lymphocyte recognition. P53 expression was detected in approximately 50% of colorectal and 25% of breast carcinomas, and in a number of colorectal carcinoma cell lines including LIF-10 and HCA-46. The p53 detected in these tumours is likely to be of mutant type. Loss of chromosome 17p alleles mapping close to the p53 locus was demonstrated in the LIF-10 and HCA-46 cell lines. In addition, loss of a chromosome 5q allele mapping close to the familial adenomatous polyposis (FAR) locus was also demonstrated in LIF-10. Finally, the expression of CD1c antigen, a molecule which shares several biochemical characteristics with HLA-A,B,C antigens, was demonstrated in normal and neoplastic B cells. The abnormalities of tumour immunoregulatory molecule expression described in this thesis may be selected for in tumour progression by conferring a selective growth advantage to tumour cells through escape from T lymphocyte attack.

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