The role of genetic drivers of DLBCL in the tumor microenvironment

Several factors influence the tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL), including genetic factors in lymphoma cells.¹ Understanding how these genetic factors influence the TME could identify novel therapeutic targets, and improve the efficacy of immunotherapies, such as chimeric antigen receptor T-cell therapies.¹

Here, we summarize a review published by Cerchietti.¹ in Blood on the role of genetic drivers of DLBCL in the lymphoma microenvironment (LME).

Classification of LME

Using artificial intelligence-based computational analysis of transcriptional signatures, researchers have identified four major categories of LMEs in DLBCL with distinct characteristics (Figure 1):

• Germinal center-like LME (GC-LME)
• Mesenchymal LME (MS-LME)
• Inflamed and immunosuppressive LME (IN-LME)
• Depleted LME (DP-LME)

ABC, activated B-cell; BCR, B-cell receptor; CAF, cancer-associated fibroblast; DLBCL, diffuse large B-cell lymphoma; DP, depleted; ECM, extracellular matrix; FDC: follicular dendritic cell; FTH, follicular T-helper cell; FRC, fibroblastic reticular cell; GC, germinal center-like; GCB, germinal center B-cell; IN, inflammatory and immunosuppressive; IRF4, interferon regulatory factor 4; JAK, Janus kinase; LME, lymphoma microenvironment; MDSC, myeloid derived suppressor cell; MS, mesenchymal;  NF-Κb, nuclear factor kappa B; NK, natural killer cell; OCT2, organic cation transporter 2; PD-1, programmed cell death-1; PI3K, phosphoinositide 3 kinase; STAT, signal transducer and activator of transcription; TAM, tumor-associated macrophage; TAN, tumor-associated neutrophil; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor; Treg, regulatory T cell; VEC, vascular endothelial cell; VLC, vascular lymphatic cell.
*Adapted from Cerchietti.¹

Impact of mutations on the TME

Mutations can affect the TME through several mechanisms, including:

• direct mutations of membrane ligands or receptors;
• mutations affecting signaling pathway transducers or scaffolding molecules; and
• expression or secretion of short- and long-range acting molecules.

The majority of genetic changes affecting the TME have a combination of direct and indirect, and short- and long-range effects on the TME, and TME changes are often influenced by multiple genetic alterations.

Direct effects on the TME

• Disruptions of antitumor immune mechanisms play a significant role in the transformation of the TME.
• The majority target the antigen processing and presentation pathway, and costimulatory and coinhibitory molecules.
  • The most common antigen processing and presentation pathway alteration in DLBCL is the lack of expression of the class I major histocompatibility complex (roughly 40–75% of patients).

Indirect effects on the TME

• Mutations that affect the transcriptional regulators (e.g., CIITA) or epigenetic regulators (e.g., EZH2, CREBBP, KMT2D, EP300) can alter the expression of ligands and receptors.

Mutations that modify the secretome and metabolism of cancer cells

• Mutations that result in the release of short- and long-range acting molecules into the extracellular space can alter the TME.
  • TP53 loss of heterozygosity and loss of function mutations can result in the modification of cellular membrane proteins and the secretome of cancer cells.

Impact of genotypic variants and alterations in non-tumor cells on the TME

• The genotypic variants and functional alterations in non-tumor cells can impact their susceptibility to reprogramming by cancer cells.
  • Age and ethnicity can be associated with differences in the TME, possibly due to functional alterations in the genome of aged cells and the presence of single nucleotide variants.

Crosstalk of cancer and LME cells during progression

• While cancer cells can alter the TME during progression, the TME conditions can also result in changes in the cancer cells. This interaction between cancer and LME cells leads to crosstalk, causing the cells to evolve in a process of co-selection.

Key learnings

The genetic characteristics of DLBCL cells can alter the TME by directly altering the expression of cell-cell signaling molecules and inducing epigenetic, metabolic, and signaling reprogramming. Given the intricacy of these interactions, the genetic constitution of the tumor is often insufficient to predict the type of TME. Elucidating the mechanism by which the genetic characteristics of DLBCL cells shape the TME may identify novel therapeutic targets.