Purpose: Novel findings point to a pathological and immunoregulatory function of IgG4 antibodies and IgG4+ B cells in inflammatory diseases and malignancies. It has been reported that IgG4 antibodies impair humoral responses and restrict activation of immune effector cells in melanoma and cholangiocarcinomas. Thus the biological function of IgG4 may also be accompanied with predictive potential.
Experimental Design: We investigated IgG4 as a potential indicator of the risk of disease progression in human sera (n=271: 167 melanoma patients; 104 healthy volunteers) and peripheral blood B cells (n=71: 47 melanoma patients; 24 healthy volunteers).
Results: The serum levels of IgG4 (IgG4/IgGtotal) were elevated in melanoma samples and high IgG4 levels correlated negatively with progression-free survival (hazard ratio (HR) 2.01, 95% confidence interval ([CI]) 1.34-3.35; P=0.0016) and overall survival (HR 1.90 95%[CI] 1.17-3.29; P=0.0116). IgG4 was an independently negative prognostic marker for progression-free survival (PFS; HR 2.46, 95%[CI] 1.01-6.02) in patients with stage I-II disease. Moreover in a similar cohort elevation of IgG4+ circulating B cells (CD45+CD22+CD19+CD3-CD14-) (P=0.014) was also negatively prognostic for progression-free survival.
The marker LDH, which is already used in clinical practice, is associated with PFS in melanoma, especially in advanced stages. We found that by combining LDH and IgG4 the prognostic value was improved (AUC:0.67; P=0.0002) than either serum indicator alone. In tissues (n=256; 108 cutaneous melanomas; 56 involved lymph nodes; 60 distant metastases; 32 normal skin samples) we found IgG4+ cell infiltrates in 42.6% of melanomas, 21.4% of involved lymph nodes and 30% of metastases. These findings suggest biological involvement of IgG4 in Th2 tumour environments at the metastatic and local levels.
Conclusion: Our data are consistent with emerging evidence for immunosuppressive roles for IgG4, further supporting prognostic utility in melanoma and potential to facilitate patient stratification.
Citation Format: Panagiotis Karagiannis, Federica Villanova, Debra H. Josephs, Isabel Correa, Mieke Van Hemelrijck, Carl Hobbs, Louise Saul, Isioma U. Egbuniwe, Isabella Tosi, Kristina M. Ilieva, Emma Kent, Eduardo Calonje, Mark Harries, Ian Fentiman, Joyce Taylor-Papadimitriou, Joy Burchel, James F. Spicer, Katie E. Lacy, Frank O. Nestle, Sophia N. Karagiannis. IgG4: a new tool to predict the risk of disease progression in melanoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A009.
- ©2016 American Association for Cancer Research.