Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival

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Abstract
Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling, mitotic index (MI), and quantification of tumor infiltrating leukocytes (TILs) and CD3+ cells in metastatic lesions to search for a molecular basis for this observation and to develop improved methods for predicting patient survival. We identified a group of 266 genes associated with postrecurrence survival. Genes positively associated with survival were predominantly immune response related (e.g., ICOS , CD3d , ZAP70 , TRAT1 , TARP , GZMK , LCK , CD2 , CXCL13 , CCL19 , CCR7 , VCAM1 ) while genes negatively associated with survival were cell proliferation related (e.g., PDE4D , CDK2 , GREF1 , NUSAP1 , SPC24 ). Furthermore, any of the 4 parameters (prevalidated gene expression signature, TILs, CD3, and in particular MI) improved the ability of Tumor, Node, Metastasis (TNM) staging to predict postrecurrence survival; MI was the most significant contributor (HR = 2.13, P = 0.0008). An immune response gene expression signature and presence of TILs and CD3+ cells signify immune surveillance as a mechanism for prolonged survival in these patients and indicate improved patient subcategorization beyond current TNM staging.