Different spatial distribution of inflammatory cells in the tumor microenvironment of ABC and GBC subgroups of diffuse large B cell lymphoma

Abstract

Diffuse Large B-Cell Lymphoma (DLBCL) presents a high clinical and biological heterogeneity, and the tumor microenvironment chracteristics are important in its progression. The aim of this study was to evaluate tumor T, B cells, macrophages and mast cells distribution in GBC and ABC DLBCL subgroups through a set of morphometric parameters allowing to provide a quantitative evaluation of the morphological features of the spatial patterns generated by these inflammatory cells. Histological ABC and GCB samples were immunostained for CD4, CD8, CD68, CD 163, and tryptase in order to determine both percentage and position of positive cells in the tissue characterizing their spatial distribution. The results evidenced that cell patterns generated by CD4-, CD8-, CD68-, CD163- and tryptase-positive cell profiles exhibited a significantly higher uniformity index in ABC than in GCB subgroup. The positive-cell distributions appeared clustered in tissues from GCB, while in tissues from ABC such a feature was lower or absent. The combinations of spatial statistics-derived parameters can lead to better predictions of tumor cell infiltration than any classical morphometric method providing a more accurate description of the functional status of the tumor, useful for patient prognosis.

High-plex imaging and cellular neighborhood spatial analysis reveals multiple immune escape and suppression patterns in diffuse large B-cell lymphoma

“…We also found immune composition differences between the two DLBCL cell-of-origin (COO) subtypes. Relative to GCB subtype samples, ABC subtype samples are more enriched for CD68−CD163+ mac-rich CNCs ( p = 0.008), while GCB samples have fewer immune-rich CNCs and more immune-sparse CNCs, which is in line with previously published data [ 9 ]. Additionally, when contrasting spatial context between ABC vs. GCB subtype, we find that the CD8-rich CNCs in ABC are more proximal to the CD68−CD163+ mac-rich ( p = 0.002) and DC-rich ( p = 0.02) CNCs (Fig.…”

Heterogeneity of the tumor immune microenvironment and its clinical relevance

“…Treating B-lineage non-Hodgkin lymphoma (NHL) with chimeric antigen receptor T (CAR-T) is a typical application of this strategy [ 136 ]. Heterogeneous mutational spectrum and spatial distribution of several immune cell types have been observed in subsets of patients with diffuse large B-cell lymphoma [ 137 , 138 ]. However, by targeting CD19, which was constitutively expressed by almost all malignant cells in DLBCL, more than half of the patients obtained durable long-term response from the CAR-T cell infusion; much higher than the objective response rate of anti-PD-1 monotherapies on DLBCL [ 139 ].…”

Diffuse large B-cell lymphoma microenvironment displays a predominant macrophage infiltrate marked by a strong inflammatory signature

“…Specifically, they showed that the presence of CD68positive tumor-infiltrating macrophages correlates with poor prognosis in the aggressive B-cell NHL subtype (7,8). Moreover, Guidolin et al (9) quantitatively evaluated the morphological features and spatial patterns (the percentage and position of positive cells in the tissue) of inflammatory cells (including macrophages) in the DLBC microenvironment. They used a morphological approach based on the estimation of an uniformity index and a spatial statistic approach that involved calculating the Ripley's K-function of the distances between cells (9).…”

“…Moreover, Guidolin et al (9) quantitatively evaluated the morphological features and spatial patterns (the percentage and position of positive cells in the tissue) of inflammatory cells (including macrophages) in the DLBC microenvironment. They used a morphological approach based on the estimation of an uniformity index and a spatial statistic approach that involved calculating the Ripley's K-function of the distances between cells (9). Their found a significantly higher immune infiltrate and uniform distribution in the more aggressive ABC subtype than in the GBC subtype (where immune cells were clustered).…”

“…The only exception concerned the distribution of CD68-positive cells that was similar in both DLBCL subtypes. These features may greatly influence the interaction of the many different cell populations within the TME and affect the distribution of key factors that drive tissue growth (9)(10)(11).…”