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

A prediction of the theory of immunologic surveillance is that tumour antig ens can be recognised by cell-mediated immunity during early development of the primary tumour by formation of tumour antigen-specific cytotoxic lymph ocytes (CTLs) and that such recognition leads to destruction of those tumou r cells (tumour regression) with subsequent appearance of tumour antigen-lo ss variants. However, this has never been shown in nonviral-induced experim ental animal models of primary malignancy or in human primary cancer. We ex amined 2 groups of human melanoma patients where primary tumour regression was observed. Twenty-three patients with multiple (greater than or equal to 3) primary melanoma showed significant histologic regression of their last tumour (median tumour regression 33%) compared to matched tumours from pati ents with a single primary melanoma (median 0%) (p = 0.008) or compared to their first primary tumour (median 0%) (p = 0.001). This increased regressi on is consistent with an "immunisation effect" seen in murine tumour transp lantation studies where innoculation with greater than or equal to3 asynchr onous tumours induces transplantation rejection on subsequent challenge. A significant decrease in MART-1-positive stained tumour area in the last pri mary 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). Metastati c tumours from 17 patients whose primary skin melanomas had completely regr essed (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 1-restricted IFN-gamma producing T lymphocytes) and MART-1 tumour antigen-loss variants was found (p = 0.001). Thus, in 2 groups of h uman melanoma subjects, we provide evidence of tumour regression associated with Melan A/MART-1 tumour antigen-loss variants correlating with formatio n of specific Melan A/MART-1 CTLs. (C) 2001 Wiley-Liss, Inc.