Primary melanoma tumour regression associated with an immune response to the tumour-associated antigen melan-A/MART-1

Abstract

A prediction of the theory of immunologic surveillance is that tumour antigens can be recognised by cell-mediated immunity during early development of the primary tumour by formation of tumour antigen-specific cytotoxic lymphocytes (CTLs) and that such recognition leads to destruction of those tumour cells (tumour regression) with subsequent appearance of tumour antigen-loss variants. However, this has never been shown in nonviral-induced experimental animal models of primary malignancy or in human primary cancer. We examined 2 groups of human melanoma patients where primary tumour regression was observed. Twenty-three patients with multiple (>/=3) primary melanoma showed significant histologic regression of their last tumour (median tumour regression 33%) compared to matched tumours from patients with a single primary melanoma (median 0%) (p = 0.008) or compared to their first primary tumour (median 0%) (p = 0.001). This increased regression is consistent with an "immunisation effect" seen in murine tumour transplantation studies where innoculation with >/=3 asynchronous tumours induces transplantation rejection on subsequent challenge. A significant decrease in MART-1-positive stained tumour area in the last primary tumour from multiple melanoma subjects (median 8%) vs. matched single melanoma patients (median 79%) (p = 0.004) and in the last vs. first tumour (median 76%) in multiple primary subjects was found (p = 0.008). Metastatic tumours from 17 patients whose primary skin melanomas had completely regressed (occult primary melanoma) also showed significant MART-1 tumour-loss variants (median 0% MART-1-positive tumour) compared to matched metastatic tumours from patients with nonregressing primary tumours (median 51%) (p = 0.001). A correlation with the presence of peripheral blood MART-1-specific CTLs (MHC class I-restricted IFN-gamma producing T lymphocytes) and MART-1 tumour antigen-loss variants was found (p = 0.001). Thus, in 2 groups of human melanoma subjects, we provide evidence of tumour regression associated with Melan A/MART-1 tumour antigen-loss variants correlating with formation of specific Melan A/MART-1 CTLs.