Follicular PD-1+ Lymphocytes in the Tumor Microenvironment Are An Independent Prognostic Factor in Follicular Lymphoma.

Abstract Abstract 134 The tumor microenvironment has been recognized as important in the pathobiology of follicular lymphoma (FL). Indeed, the role of extrafollicular lymphoma-associated macrophages (ef-LAMs) and FOXP3+ regulatory T-cells (Tregs) as predictors of overall survival in FL was previously reported by our group and others. We sought to further evaluate the role of specific T-cell subsets in our patient series. To this end we enumerated PD-1+ follicular helper T-cells (Tfhs), a potentially important regulator of immune response, in the tumor microenvironment in a series of 91 newly diagnosed FLs. Initial biopsies from 91 FL patients diagnosed between 9/1/85 and 12/13/02 were evaluated. FL grade 3B cases were excluded. Clinical data was obtained for gender, age, FLIPI risk group, presence of bulky disease, presence of B-symptoms and overall survival (OS). Immunohistochemical staining for PD-1 was performed on tissue microarray sections and the mean number of follicular PD-1+ cells per 9 high power fields (1000x, 3 follicles with 3 fields per follicle) was quantified. Recursive partitioning analysis was then performed to determine an optimal break-point for PD-1. BCL2 expression, ef-LAMs and FOXP3+ Tregs were evaluated as reported by us previously. The Cox proportional hazards model was used to determine significant univariate and multivariate prognostic risk factors, using P≤ 0.10 as the criterion for inclusion and retention in the multivariate analysis. The Kaplan-Meier method was used to summarize OS. 54% of patients were male with a median age at diagnosis of 58 years (range 24–89 years). The distribution of FLIPI scores was 35% low, 27% intermediate, and 37% high. The number of PD-1+ Tfhs was variable (median number of PD-1+ cells = 35.6, range 4.4 – 91.2). Number of PD-1+ cells correlated with number of Tregs (P=.01) and marginally with lack of BCL2 (P=.07) but not with other clinical or pathologic variables. On univariate analysis, age ≥ 55 (P=0.004), increasing FLIPI risk group (P=0.03), bulky disease (>10 cm; P=0.05), lack of BCL2 (P=.01), high ef-LAMs (>16.8/hpf, P=.003), and high PD-1+ cells (>35.6/hpf, P=0.10) were all associated with decreased OS. On multivariate analysis, independent poor prognostic risk factors were: age ≥55 (hazard ratio[HR]=2.76, 95% confidence interval [CI] = 1.33–5.76, P=.007), high ef-LAMs (HR=2.13, 95%CI = 1.11–4.07, P=.02) bulky disease (HR=2.10, 95% CI 0.91–4.83, P=.08), and high PD-1+ cells (HR 2.04, 95% CI=1.11–3.75, P=.02). A prognostic model based on the number of risk factors present can be constructed with patients having 0, 1-2 or 3-4 risk factors defining 3 distinct prognostic groups ( Figure 1 ). In summary, cellular constituents of the FL microenvironment play an important role in the biology of FL. A combination of standard clinical and biologic factors that include Tfhs and ef-LAMs appear to predict OS in FL. Given the putative role for Tfhs in down-regulating the immune response, these data support strategies aimed at modulating Tfh function in FL. Download : Download high-res image (124KB) Download : Download full-size image Disclosures: No relevant conflicts of interest to declare.