Cancer–testis antigen expression in primary cutaneous melanoma has independent prognostic value comparable to that of Breslow thickness, ulceration and mitotic rate*
Introduction
Cutaneous melanoma is a major and increasing public health issue worldwide and its incidence continues to rise in individuals of European origin.1 In the United States it is predicted to be the fifth and sixth most common cancer in men and women, respectively, in 2009.2 Wide local excision of the primary tumour is currently the standard treatment for cutaneous melanoma3 and is successful particularly for patients with thin tumours.4 In many melanoma treatment centres, sentinel lymph node biopsy is offered to patients with melanomas >1 mm thick or to those with melanomas <1 mm thick if other adverse prognostic factors are present. Surgery is also considered the mainstay for treating melanoma that has metastasised to regional lymph nodes.5 For patients with widespread metastatic disease, the outcome is poor,4 single agent or combination chemotherapy has little efficacy6 and at present treatment is directed at palliation of symptoms rather than curing the tumour.7
With such limited therapeutic options for advanced metastatic disease, interest in vaccine development is high. Antigens that are relatively specific for cancer, known as cancer–testis antigens (CTAgs), have been demonstrated to serve as targets through their presentation on HLA molecules for immune recognition by cytotoxic T lymphocytes (CTLs).8 CTAgs are expressed by many different tumours as well as by spermatogonia and trophoblast but not by other normal somatic cells.9 Previous work involving CTAgs has focused on assessment of the expression patterns of these antigens in cancers10, 11, 12 as well as the development, use and immune response monitoring of cancer vaccines in the clinical setting.13 However, very little is currently known about the correlation of CTAg expression with clinical data, such as known prognostic factors and survival in melanoma patients. Most previous studies are disadvantaged by the small number of tumours studied and/or the limited numbers of antigens tested.12, 14
This study assessed CTAg expression in a large series of primary cutaneous melanomas and correlated the expression of these antigens with other clinico-pathologic features, relapse free survival (RFS) and overall survival (OS).
Section snippets
Patients and clinical specimens
Archival formalin-fixed, paraffin-embedded tissue blocks of stage I or stage II primary cutaneous melanomas from patients treated at the Austin Health Melanoma Clinic (Melbourne, Australia) or the Melanoma Institute Australia (MIA) (Sydney, Australia) were retrieved. Sections were cut and stained with haematoxylin–eosin to confirm the diagnosis of primary melanoma and then immunohistochemistry was performed as described below. All protocols were approved by the Austin Health Human Research
Patients
In total, 348 primary stage I and II cutaneous melanomas were collected and typed for CTAg expression. These included 271 melanoma patients treated at the Austin Health Melanoma Clinic between 1994 and 2008, and 77 patients treated at the MIA between 1992 and 2004. Of these, 250 Austin tumours and 71 MIA tumours had complete clinical data and were subsequently included in the clinicopathologic/CTAg analysis (Table 1). Only stage II tumours were analysed for RFS (Fig. 2 and Table 2) and OS (Fig.
Discussion
The molecular analysis of melanoma is proving to be increasingly important for understanding subclassification and for determining optimal treatment. The CTAgs have proven to be of particular interest because they are targets for immune recognition and therefore immunotherapy.13 Little is known about their function and influence on the behaviour of melanoma, so we have performed the first detailed study that relates the expression of these key molecules to clinical outcomes.
Although there was
Conflict of interest statement
None declared.
Acknowledgements
The following Austin Health medical oncology fellows contributed patient tumours to this study: Mark Shackleton, Phillip Parente, Catherine Barrow and Oliver Klein. We also thank Sunanta Lee and Belinda Rutledge who created and maintain the melanoma database. I.D.D. is supported in part by a Victorian Cancer Agency Clinical Researcher Fellowship and is an Australian National Health and Medical Research Council (NHMRC) Honorary Practitioner Fellow. J.C. is an NHMRC Practitioner Fellow. R.A.S.
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Chemical complementarity between tumor resident, T-cell receptor CDR3s and MAGEA3/6 correlates with increased melanoma survival: Potential relevance to MAGE vaccine auto-reactivity
2022, Molecular ImmunologyCitation Excerpt :MAGEA3 and MAGEA6 in particular have been shown to be involved in altering ubiquitin protease activity in tumors (Weon and Potts, 2015; Yang et al., 2007; Lee and Potts, 2017). The MAGE gene family overall has had a long history of importance in prognosis and therapy, e.g., expression levels in primary cutaneous melanoma can have a prognostic value similar to Breslow thickness, mitotic rate, and ulceration (Svobodova et al., 2011). Thus, in applying the CS algorithms for tumor resident TCR CDR3s and the MAGEA3/6 CTAs, we determined that such CSs represented clear patient survival distinctions and very efficiently pointed to sub-sequences within the MAGEA3/6 proteins that could serve as effective melanoma antigenic targets, possibly avoiding the previous complications of vaccine auto-reactivity and heart failure (Linette et al., 2013; Cameron et al., 2013) and neurotoxicity (Morgan et al., 2013; Chinnasamy et al., 2011).
The “-OMICS” facet of melanoma: Heterogeneity of genomic, proteomic and metabolomic biomarkers
2019, Seminars in Cancer BiologyCitation Excerpt :The same studies highlighted the heterogeneity of NY-ESO-1 expression in melanoma cells in both primary and metastatic melanomas, with the spectrum of positivity ranging from only a small percentage of cells to diffuse positivity [75,76]. These are important limiting factors that could have contributed to the conflicting results of studies that evaluate the association between with NY-ESO-1 and survival in MM [64,74–76]. Cancer-associated fibroblasts (CAFs) play an important role in melanoma tumorigenesis; they have emerged in the last couple of years as potential therapeutic targets [77].
Phase II trial of ipilimumab in melanoma patients with preexisting humoural immune response to NY-ESO-1
2018, European Journal of CancerCitation Excerpt :NY-ESO-1 elicits spontaneous humoural and cellular responses in many patients with cancer [10]. Data regarding the prognostic effect of cancer/testis antigen expression in melanoma patients are conflicting: an inferior outcome in early-stage patients with cancer/testis antigen expressing tumours or with antibody responses against cancer/testis antigens has been reported [11,12], whereas the presence of functional NY-ESO-1–specific T-cells correlated with a superior survival in patients with metastatic melanoma [13]. In patients receiving ipilimumab, the predictive role of NY-ESO-1 preexisting immune responses is unclear: Yuan et al. [14,15] observed a higher response rate and a superior survival in patients being seropositive for NY-ESO-1, whereas Goff et al.[16] could not confirm the higher efficacy of ipilimumab in NY-ESO-1 seropositive patients.
Prognostic factors for metastasis in cutaneous melanoma
2018, Anais Brasileiros de DermatologiaCombinational expression of tumor testis antigens NY-ESO-1, MAGE-A3, and MAGE-A4 predicts response to immunotherapy in mucosal melanoma patients
2023, Journal of Cancer Research and Clinical Oncology
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This work was conducted as part of the Hilton–Ludwig Cancer Metastasis Initiative, funded by the Conrad N. Hilton Foundation and the Ludwig Insitute for Cancer Research.