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Published on: March 7, 2025
Autonomous histopathological regression of primary tumours associated with specific immune responses to cancer
Farid H Saleh1, Kerry A Crotty, Peter Hersey
1Department of Human Morphology, Faculty of Medicine, The American University of Beirut, PO Box 11-0236, Beirut, Lebanon. FaridS l h@netscape.net
Abstract:
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.
Insights
This study provides evidence for cancer immune surveillance in melanoma patients. It shows that multiple primary melanomas are associated with tumor regression and loss of the MART-1 antigen, suggesting an immune response.
Area of Science:
- Immunology
- Oncology
- Dermatology
Background:
- Spontaneous cancer regression suggests immune system involvement, known as cancer immune surveillance.
- A key prediction is that repeated exposure to tumor antigens can elicit cell-mediated immunity, leading to tumor regression and antigen-loss variants.
- Direct evidence for this in human primary cancers has been lacking.
Purpose of the Study:
- To investigate histopathological regression of primary melanoma in relation to immune surveillance.
- To examine the expression of melanoma antigens, particularly MART-1, in patients with multiple primary melanomas and occult primary melanomas.
- To correlate tumor antigen loss with the presence of tumor-specific cytotoxic T lymphocytes (CTLs).
Main Methods:
- Analysis of histopathological regression in two groups of melanoma patients: those with multiple primary melanomas and those with single primary melanomas.
- Comparison of MART-1 antigen expression in primary tumors and metastases between patient groups.
- Assessment of MART-1-specific CTLs in peripheral blood and correlation with antigen loss.
Main Results:
- Patients with multiple primary melanomas showed significantly greater regression of their last melanoma compared to single melanoma patients or their own first melanoma.
- A significant decrease in MART-1 antigen expression was observed in the last primary tumors of multiple melanoma patients and in occult primary melanomas.
- MART-1 antigen loss correlated with the presence of MART-1-specific CTLs in peripheral blood.
Conclusions:
- The findings provide evidence for histopathological tumor regression associated with cancer immune surveillance in human melanoma.
- The study supports the theory that repeated exposure to tumor antigens can lead to immune-mediated tumor regression and antigen loss.
- MART-1 appears to be a key antigen involved in this immune surveillance mechanism in melanoma.
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