Follicular programmed death 1–positive lymphocytes in the tumor microenvironment are an independent prognostic factor in follicular lymphoma

SummaryWe enumerated programmed death 1 (PD-1)-positive follicular helper T cells, a potentially important regulator of immune response, in the tumor microenvironment of a series of 91 newly diagnosed follicular lymphomas managed at a single institution. Clinical data were obtained for sex, age, Follicular Lymphoma International Prognostic Index (FLIPI) risk group, presence of bulky disease, presence of B symptoms, and overall survival. Immunohistochemical staining for PD-1 was performed on tissue microarray sections, and the mean number of follicular PD-1-positive cells per 9 high-power fields (1000×, 3 follicles with 3 fields per follicle) was quantified. B-cell CLL/lymphoma 2 (BCL-2) expression, CD68+ extrafollicular lymphoma-associated macrophages, and forkhead box P3 (FOXP3)+ regulatory T cells were evaluated as reported previously. Ninety-one patients were evaluated, with a median age at diagnosis of 58 years and median survival of 11.6 years. PD-1-positive cells correlated with the number of FOXP3+ regulatory T cells (P = .01). On multivariate analysis, independent poor prognostic factors were age 55 years or greater (hazard ratio, 2.77; 95% confidence interval, 1.34-5.73; P = .006), bulky disease (hazard ratio, 2.27; 95% confidence interval, 1.03-5.00; P = .04), CD68+ extrafollicular lymphoma-associated macrophages greater than 16.8 cells/high-power field (hazard ratio, 2.15; 95% confidence interval, 1.14-4.06; P = .02), and PD-1-positive cells greater than 35.6 cells/high-power field (hazard ratio, 1.98; 95% confidence interval, 1.09-3.60; P = .03). These factors allowed construction of a risk score defining 3 distinct prognostic groups with 10-year overall survival of 85%, 60%, and 15%. PD-1-positive follicular helper T cells and CD68+ extrafollicular lymphoma-associated macrophages appear to predict overall survival in follicular lymphoma, and our findings support strategies aimed at modulating their function in follicular lymphoma. Future studies, performed prospectively on uniformly treated patient cohorts, should be performed to validate these findings.