Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pSTAT3 expression in AJCC stage I/II melanoma

Abstract

Tumor cell and host immune cell interaction plays a key role in carcinogenesis. Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in cancer and believed to be an important mediator of tumor-induced immunosuppression. This paper aims to describe the prognostic impact of neutrophil and dendritic cell infiltration in primary melanoma and the association of this infiltration with activated STAT3 (pSTAT3) in primary melanoma cells. Formalin-fixed, paraffin-embedded primary melanomas from 186 stage-I/II melanoma patients surgically resected from 1997 to 2000. Infiltrating neutrophils (CD66b), dendritic cells (CD123+ and DC-LAMP+), T-lymphocytes (CD8) and pSTAT3 melanoma cell expression were studied by immunohistochemistry and evaluated as present or absent. DC-LAMP+ cell infiltration was evaluated as absent/few versus dense. Study endpoints: relapse-free survival, melanoma-specific, and overall survival. The median observation time was 12.2 years (range, 10.4-14.2 years). Fifty-one deaths were observed of which 38 (20%) were melanoma-specific. In a multivariate Cox proportional hazards model including ulceration and melanoma thickness, neutrophil and CD123+ dendritic cell infiltration were independently associated with poor prognosis (CD66b: hazard ratio [HR] = 3.13; 95% confidence interval [CI], 1.43-6.83; P = .004; CD123: HR = 2.45; 95% CI, 1.22-4.92; P = .012). The association between melanoma cell pSTAT3 expression and immune infiltration (neutrophils and CD123+ cells) was strong. pSTAT3 expression, CD8 and DC-LAMP infiltration were not independently associated with poor prognosis. Neutrophil infiltration and CD123+ dendritic cell infiltration in primary melanoma are independently associated with poor prognosis. Melanoma cell expression of pSTAT3 is strongly associated with the surrounding immune infiltrate.