Immunologic heterogeneity of tumor-infiltrating lymphocyte composition in primary melanoma

Tumor-infiltrating lymphocytes (TILs) in primary melanomas are thought to represent the host antitumor immune response, but controversy exists over whether TILs offer independent prognostication of survival. We studied a cohort of 1241 patients with primary melanoma to assess the association of absent, nonbrisk, and brisk TIL grade with survival outcomes. We tested whether quantitative TIL counts using immunohistochemical lymphocyte markers CD3, CD45, and FOXP3 add prognostic value to TIL grading compared with histology alone in 15% of the cohort. To assess for intergroup immunologic heterogeneity among TIL grades, we investigated differential expression of 594 immunoregulatory genes in 67 primary melanomas. On histologic evaluation of 1241 primary melanomas, TILs were graded as absent (n=388, 31%), nonbrisk (n=330, 27%), and brisk (n=523, 42%). Patients with brisk TILs had improved recurrence-free survival (P=.025) and overall survival (P=.006) compared with patients with nonbrisk and absent TILs, for which there were no differences in recurrence-free survival (P=.40) or overall survival (P=.41). TIL quantitation by immunohistochemistry did not improve prognostication compared with TIL grading on hematoxylin and eosin-stained sections. Melanomas with nonbrisk and absent TILs share similar immunoregulatory gene expression profiles. In contrast, melanomas with brisk TILs demonstrate upregulation of T-cell activation pathways and inhibition of upstream immune checkpoint regulators. The presence of TILs in primary melanomas represents a heterogeneous group, and caution in prognostic interpretation is warranted. Melanomas with brisk TILs are defined by an immunostimulatory gene expression profile and improved prognosis compared with melanomas with nonbrisk or absent TILs.