Expression of PD-1 (CD279) and FoxP3 in diffuse large B-cell lymphoma

Abstract

The role of the microenvironment in high-grade lymphoma is not well defined. In this report, we employ immunohistochemistry to characterise programmed death-1 (PD-1/CD279) and FoxP3 expression in 70 cases of diffuse large B-cell lymphoma (DLBCL). PD-1 is a surface marker characteristic of follicular helper T-cells whilst FoxP3 is characteristic of Tregs. We demonstrate variable infiltration with CD4(+) T-cells (<10 to >50 % of all lymph node cells) and PD-1(hi) cells (0.1 to 1.5 % of all cells). CD4(+) T-cells can be distributed in clusters or more diffusely and PD-1(hi) cells, but not FoxP3(+) cells, are found in rosettes around lymphoma cells. Cases with high CD4(+) T-cell numbers tended to have higher numbers of both PD-1(hi) and FoxP3(+) cells. Cases with total CD4(+) T-cell, PD-1(hi) and FoxP3(+) numbers above the median associate with better clinical outcome. Overall, we demonstrate that infiltration by CD4(+) T-cells, including both FoxP3(+) and PD-1(hi) subsets, correlates with prognosis in DLBCL. In distinction to previous reported series, patients (91 %) were treated with rituximab-containing regimens, suggesting that the effects of CD4+ T-cell infiltration are maintained in the rituximab era. This work suggests that determinants of total CD4(+) T-cell infiltration, either molecular characteristics of the lymphoma or the patients' immune system, and not individual T-cell subsets, correlate with clinical outcome.

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?

“…75 It is also likely that biological behavior and prognosis are determined not only by overall PD-1 + TILs and tumor cells, but by functionally distinct subsets. PD-1 + numbers correlated with CD4 + T-cell and FoxP3 + numbers and GrB and TIA-1 + cells in several studies, 42,52,72 and similar associations were found between distribution patterns of FoxP3 + and PD-1 + cells. Modulating effects might also be exerted by other microenvironment components such as TAMs, 35 tumor-associated histiocytes, 37 and small vessels.…”

“…While actual median values were not reported, the numbers of PD1 + T FH (P=0.0007), FoxP3 + (P=0.0069), and total CD4 + cells (P=0.04) above the median were associated with improved overall survival (OS), and had independent prognostic significance in multivariate analyses. 42 This was confirmed in more recent studies; although the quantity of PD-1 + TILs showed no significant association with clinicopathological variables, the presence of PD-1 + TILs (score 1-3) significantly prolonged OS (P=0.026) and progression-free survival (PFS) (P=0.005), and was an independent favorable prognostic factor in multivariate analyses. 38 In contrast, in another study, patients with PD-1 expression >20/hpf had a trend to poorer OS (P=0.120).…”

“…41 More than half of the included patients were classified PD-1 + , with no differences between GCB subtypes. 42 More recently, PD-1 was detected on TILs in all but two cases, and their quantity correlated positively with the level of PD-L1 expression in tumor cells (P=0.042) or in tumor cells/macrophages (P=0.03). 38 In the study by Kiyasu et al, the number of PD-1 + TILs was significantly lower in PD-L1 + patients and in those with B symptoms (P=0.024), extranodal sites (P=0.042) and bulky disease (P=0.041), but higher in GCB-type DLBCL (P=0.034).…”

Programmed cell death protein 1 expression is an independent prognostic factor in gastric cancer after curative resection

“…PD-1 and its ligand, programmed cell death ligand 1 (PD-L1), interact to downregulate the activation of T cells in autoimmune disease, chronic infection, and cancer [4,5]. PD-1 is also known to activate the transcription factor Foxp3, and is correlated with Foxp3 expression [6]. Several recent reports have demonstrated a correlation between PD-1 expression and prognosis in cancer patients.…”

The expression and clinical relevance of PD-1, PD-L1, and TP63 in patients with diffuse large B-cell lymphoma

“…[14,15] In diffuse large B-cell lymphoma (DLBCL), PD-1 was expressed on tumor-infiltrating lymphocytes (TILs), and the number of PD-1 + TILs was associated with the favorable overall survival (OS) in patients with DLBCL. [16,17] Besides, the higher expression of PD-L1 was also found in tumor cells and it maybe a potential biomarker for DLBCL. [18] Thus, the PD-1/PD-L1 pathway may also contribute to the proliferation of tumor cells of DLBCL and may be a novel applicable strategy to treat patients with DLBCL.…”