1. Human melanoma metastases demonstrate nonstochastic site-specific antigen heterogeneity that correlates with T-cell infiltration.
- Author
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Bartlett EK, Fetsch PA, Filie AC, Abati A, Steinberg SM, Wunderlich JR, White DE, Stephens DJ, Marincola FM, Rosenberg SA, and Kammula US
- Subjects
- CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes pathology, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes pathology, Cluster Analysis, Cohort Studies, Histocompatibility Antigens Class I metabolism, Histocompatibility Antigens Class II metabolism, Humans, Immunohistochemistry, Lymphocytes, Tumor-Infiltrating pathology, MART-1 Antigen metabolism, Melanoma pathology, Melanoma-Specific Antigens classification, Monophenol Monooxygenase metabolism, Neoplasm Metastasis, T-Lymphocytes pathology, gp100 Melanoma Antigen metabolism, Lymphocytes, Tumor-Infiltrating metabolism, Melanoma metabolism, Melanoma-Specific Antigens metabolism, T-Lymphocytes metabolism
- Abstract
Purpose: Metastasis heterogeneity presents a significant obstacle to the development of targeted cancer therapeutics. In this study, we sought to establish from a large series of human melanoma metastases whether there exists a determined pattern in tumor cellular heterogeneity that may guide the development of future targeted immunotherapies., Experimental Design: From a cohort of 1,514 patients with metastatic melanoma, biopsies were procured over a 17-year period from 3,086 metastatic tumors involving various anatomic sites. To allow specific tumor cell profiling, we used established immunohistochemical methods to perform semiquantitative assessment for a panel of prototypic melanocyte differentiation antigens (MDA), including gp100, MART-1, and tyrosinase. To gain insight into the endogenous host immune response against these tumors, we further characterized tumor cell expression of MHC I and MHC II and, also, the concomitant CD4(+) and CD8(+) T-cell infiltrate., Results: Tumor cell profiling for MDA expression demonstrated an anatomic site-specific pattern of antigen expression that was highest in brain, intermediate in soft tissues/lymph nodes, and lowest in visceral metastases. Hierarchical clustering analysis supported that melanoma metastases have a phylogenetically determined, rather than a stochastic, pattern of antigen expression that varies by anatomic site. Furthermore, tyrosinase expression was more frequently lost in metastatic sites outside of the brain and was uniquely correlated with both endogenous CD8(+) and CD4(+) T-cell infiltrates., Conclusion: Site-specific antigen heterogeneity represents a novel attribute for human melanoma metastases that should be considered in future therapy development and when assessing the responsiveness to antigen-specific immunotherapies., (©2014 American Association for Cancer Research.)
- Published
- 2014
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