Prognostic significance of programmed cell death‐1‐positive cells in follicular lymphoma patients may alter in the rituximab era

Abstract

Programmed cell death-1 (PD-1) is involved in one of the inhibitory pathways of the B7-cluster of differentiation (CD) 28 family; this pathway is known to be involved in the attenuation of T-cell responses and promotion of T-cell tolerance. PD-1 is known to negatively regulate T-cell receptor-mediated proliferation and cytokine production, lead to alternation in the tumor microenvironment. Although several studies have shown that high levels of PD-1-positive cells in follicular lymphoma (FL) patients influence their prognosis, those studies included patients treated without rituximab, and the prognostic impact of PD-1 positivity in the rituximab era (R-era) has not yet been elucidated. We retrospectively studied 82 patients with FL uniformly treated with standard R-CHOP therapy at six institutions between 2001 and 2009 (median follow-up for survivors: 55 months). We also collected and examined biopsy specimens for diagnosis with respect to PD-1 positivity. The PD-1 positivity was significantly higher in male patients and patients with high beta-2 microglobulin (B2M ≥ 3.0) (P = 0.03 and 0.003, respectively). Three-year progression free survival (PFS) and overall survival (OS) were 60% and 86%, respectively. By univariate analysis, elevated LDH (P = 0.07) worsened PFS. Male gender (P = 0.03), high FLIPI score (P = 0.05), and high B2M levels (P = 0.08) worsened OS. Multivariate analysis detected no significant prognostic factors, including PD-1 positivity. However, in male subgroup, high levels of PD-1-positive cells were found to be a prognostic factor for PFS. Addition of rituximab might have altered the prognostic impact of PD-1-positive cells.

PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

“…This was even more surprising, given that PD-1 þ TIL were positively associated with disease grade in both the HGSC and endometrioid subtypes. However, similar to our findings, PD-1 þ TIL have been associated with favorable prognosis in HPV þ head and neck cancer (45) and follicular lymphoma (46)(47)(48). On the other hand, PD-1 þ TIL have been associated with poor prognosis in breast and renal cancer (8,(10)(11)(12).…”

Prognostic relevance of CD163 and CD8 combined with EZH2 and gain of chromosome 18 in follicular lymphoma: a study by the Lunenburg Lymphoma Biomarker Consortium

“…However, the positive prognostic value of PD1+ cells was seen in studies in which only some of the patients received rituximab, 16,22 whereas in studies in which the majority of patients were treated with rituximab-chemotherapy, either no effect or a negative effect was reported. 39,41 Frequencies of mutations and distribution of alterations in hotspots and functional domains of the tested genes are largely in line with those previously reported. 28,31,[48][49][50] Almost all FLs are reported to have mutations in 1 or more histone-modifying gene, such as KMT2D (reported as 76-89%), CREBBP (reported as 33-68%), MEF2B (reported as 15%), EP300 (reported as 9-15%) and EZH2 (reported as 7-26%).…”

“…Of equal importance, in the study herein we could not substantiate the previously reported claims on the prognostic impact of the other most commonly mutated genes, such as TNFRSF14 and EP300, of T-cell populations and classes of macrophages, as well as a perifollicular distribution of FOXP3+ T cells for patients treated with R-CHOP (-like). 14,16,18,22,24,31,[39][40][41]54 Moreover, the study herein provides further insight into the relationship between gene mutation status and the most relevant microenvironmental populations in FL. …”

“…Equally important, cellular densities of various other cell populations, such as PD1+ T follicular helper (T FH ) cells and FOXP3+ T regulatory (Treg) cells, previously claimed to predict clinical outcome, were not confirmed in our study. 16,22,24,[39][40][41] This study was specifically designed to verify the impact of previously published IHC and molecular markers in FL in the rituximab-chemotherapy era. Therefore, we implemented a dedicated study design to reduce noise such that all cases were retrieved from clinical trials and registries which guaranteed complete clinical information at presentation and detailed treatment information.…”

Catching up with solid tumor oncology: what is the evidence for a prognostic role of programmed cell death-ligand 1/programmed cell death-1 expression in B-cell lymphomas?

“…Decreasing but numerous PD-1 + TILs with increasing grade (n=49) and transformation to DLBCL (n=11) were described by others. 40 There might be an association between male gender and increased PD-1 + cells, 51 but further confirmation is lacking. Several studies have focused on localization patterns of TFH cells.…”