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. Twentythree 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-␥ 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.

Spontaneous histopathological regression of cancer has been reported. The involvement of the immune system in such regression has been advocated, leading to the theory of immunological surveillance against cancer. A prediction of this theory is that common tumour antigens can be recognized upon repeated exposure by cell-mediated immunity, which leads to tumour regression and the subsequent appearance of tumour antigen-loss variants. However, no direct evidence has been provided in non-viral-induced experimental animal models of primary malignancy or in human primary cancer. This study examined two groups of melanoma patients where histopathological regression of the primary tumour was observed. Many of the 23 patients with multiple (> or =3) primary melanomas showed significant regression of their last melanoma (median 33%, mean 40) compared with matched melanomas from patients with a single primary melanoma (median 0%, mean 12) (p=0.0080), or compared with their first primary melanoma (p=0.0013). Regression was consistent with an 'immunization effect' seen in murine tumour transplantation studies, where inoculation with > or =3 asynchronous tumours induces transplantation rejection on subsequent challenge. A significant decrease in the expression of the melanoma common tumour antigen MART-1 in the last primary tumour from multiple melanoma patients (median 8%, mean 24) versus matched single melanoma patients (median 79%, mean 68) (p=0.0041) and in the last versus first tumour in multiple primary patients was found (p=0.0083). Metastases from 17 patients whose primary skin melanomas had completely regressed (occult primary melanoma) also showed significant MART-1 loss (median 0%, mean 11) compared with matched metastases from patients with non-regressing primary melanoma (median 51%, mean 50) (p=0.0013). MART-1 antigen-loss variants observed in the multiple primary and occult primary patients correlated with the presence of peripheral blood MART-1-specific cytotoxic T lymphocytes (CTLs) (p=0.03). No similar effects were observed with two other melanoma antigens, gp100 and CD63. Thus, in two groups of human melanoma patients, evidence is provided for histopathological tumour regression associated with cancer immune surveillance.

BackgroundCancer immunotherapy requires proper manipulation of the immune system, lymphocytes in particular, in order to identify and destroy the cancer cells as non-self. In this study we investigated the effect of the flavonoid present in green tea, namely epigallocatechin-3-gallate (EGCG), on the proliferation of, and IFN-γ production by, peripheral blood mononuclear cells (PBMC) from breast cancer patients stimulated with a mitogen, anti-CD3 and the common breast cancer peptides Her-2/neu, and p53.MethodsBlood samples were collected from 25 patients with breast cancer at the Kuwait Cancer Control Centre (KCCC). The patients were newly diagnosed, and had not undergone any treatment or surgery at the time of sample collection. The control group consisted of 25 healthy women age-matched (±5 years) to the patients. PBMC were isolated from the patients and controls, and were cultured separately with the mitogen PHA, anti-CD3 antibodies, and Her-2/neu and p53 in the presence or absence of standardized doses of EGCG. The degree of proliferation and interferon-γ [IFN-γ) release were then analyzed.ResultsEGCG significantly suppressed the proliferation of PBMC in response to stimulation separately with (i) the mitogen, (ii) anti-CD3, and (iii) the cancer antigen peptides. IFN-γ production was also significantly suppressed by EGCG in vitro.ConclusionsEGCG appears to have an immunosuppressive effect on the proliferation of PBMC, indicating that EGCG is worth exploring for immunomodulatory effects in autoimmune diseases and tissue transplantation.

It is not clear whether some pathological changes in hypertension are directly pressure-dependent, or hormonally induced, or both. The aortic arch has apparently never before been studied for those changes. The aim of this study was to compare the effects of controlling angiotensin II (Ang II) and/or blood pressure (BP), directly at the inception of hypertension, on the aortic arch, the left ventricle of the heart (LV), and the kidneys of spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto (WKY) rats. An angiotensin-converting enzyme inhibitor (ACEI, enalapril) and a calcium-channel blocker (nifedipine) were used for 21 weeks. After treatment, rats were assessed for arterial plasma renin activity (PRA). The LV, aortic arch, and kidneys were then excised for the determination of organ and tissue weight in some of the animals, while in others the aortic arch was fixed in situ and processed for microscopic analysis. Both enalapril and nifedipine levelled BP in the SHRs to almost normal values. Enalapril was able to prevent the increase in LV and kidney weights (p=0.04 wet, p<0.001 dry; p<0.001 wet and dry, respectively) and the increase in the weight of the aortic arch and in the thickness of its media (p<0.001 wet and dry; p<0.001, respectively) seen in untreated SHRs. This was associated with a larger lumen diameter (p<0.001) and a lower media to lumen ratio (p=0.01). In contrast, nifedipine did not prevent any of the changes described. Neither nifedipine nor enalapril treatment had any effects on PRA in either rat strain. Our results support previous observations that BP is not the only factor causing some of the pathological changes in hypertension; tissue Ang II level may also play a major role.