The tumour microenvironment influences survival and time to transformation in follicular lymphoma in the rituximab era

Abstract

The tumour microenvironment influences outcome in patients with follicular lymphoma (FL), but its impact on transformation is less studied. We investigated the prognostic significance of the tumour microenvironment on transformation and survival in FL patients treated in the rituximab era. We examined diagnostic and transformed biopsies from 52 FL patients using antibodies against CD3, CD4, CD8, CD21 (CR2), CD57 (B3GAT1), CD68, FOXP3, TIA1, PD-1 (PDCD1), PD-L1 (CD274) and PAX5. Results were compared with a second cohort of 40 FL patients without signs of transformation during a minimum of five years observation time. Cell numbers and localization were semi-quantitatively assessed. Better developed CD21+ follicular dendritic cell (FDC) meshworks at diagnosis was a negative prognostic factor for overall survival (OS), progression-free survival (PFS) and time to transformation (TTT) in patients with subsequently transformed FL. Remnants of FDC meshworks at transformation were associated with shorter OS and PFS from transformation. High degrees of intrafollicular CD68+ and PD-L1+ macrophage infiltration, high total area scores and an extrafollicular/diffuse pattern of FOXP3+ T cells and high intrafollicular scores of CD4+ T cells at diagnosis were associated with shorter TTT. Scores of several T-cell subset markers from the combined patient cohorts were predictive for transformation, especially CD4 and CD57.

CD274 (PD‐L1)/PDCD1 (PD‐1) expression in de novo and transformed diffuse large B‐cell lymphoma

“…In summary, although in general agreement with previous reports (Kiyasu et al , ; Blaker et al , ; Georgiou et al , ; Menter et al , ), our data expand substantially on those studies. We show for the first time that, in DLBCL, the SP142 antibody correlates in an absolute manner with CD274/PDCD1LG2 gene amplification status assessed by FISH, but generally fails to detect low/moderate levels of the protein.…”

“…We read with interest the paper by Blaker et al (), which reported that several factors of the tumour microenvironment are associated with patient survival and time to transformation in follicular lymphoma (FL). In particular, the authors investigated the impact of PDCD1 (PD‐1)‐positive tumour infiltrating T‐lymphocytes (TILs) and CD274 (PD‐L1)‐positive macrophages in a cohort of transformed FLs using a single antibody for CD274.…”

“…(Sharma & Allison, ) Furthermore, increased numbers of CD274 positive histiocytes correlated with superior overall survival ( P = 0·049 by Kaplan‐Mayer method and Log rank test, Fig ) despite the small number of patients in this cohort. Blaker et al () reported that high numbers of intrafollicular CD68+ and CD274+ histiocytes correlated with shorter time to transformation of FL but not with survival of the patients.…”

Differential expression of estrogen receptor–α on follicular dendritic cells from patients with grade 1‐2 and grade 3 follicular lymphoma

“…Follicular lymphoma (FL) is a GC‐derived lymphoma that frequently follows an indolent clinical course . Although FL is responsive to initial chemotherapy, late relapses are common .…”

Highly Tumorigenic Diffuse Large B Cell Lymphoma Cells Are Produced by Coculture with Stromal Cells

“…High infiltration of CD8+ T cells in tumor specimens is related to the inferior overall survival rate of DLBCL [13]. High degrees of intrafollicular CD68+ and programmed cell death ligand 1+ macrophage infiltration are associated with a shorter time to transformation in FL [14]. Furthermore, cancer stem cells or the tumor-initiating cells of BCL maintain their tumorigenic potential via interplay with the TME [15, 16].…”