Tumor Microenvironment, Inflammation, and Inflammatory Prognostic Indices in Diffuse Large B-Cell Lymphomas: A Narrative Review

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, characterized by significant variability in clinical outcomes. Emerging evidence highlights the pivotal role of inflammation in the pathogenesis and prognosis of DLBCL. This narrative review explores the interplay between the tumor microenvironment, inflammatory processes, and prognostic indices used in DLBCL, focusing on biomarkers, immune responses, and systemic inflammation. These indices show promise as predictive and prognostic tools comparable to molecular markers, such as gene expression profiling, which are currently considered gold standards in prognosis but are often costly and technically demanding. By synthesizing findings from the current literature, this article highlights the potential of inflammatory indices as accessible and cost-effective prognostic alternatives to molecular markers in DLBCL, while also underscoring the need for further research to validate their clinical utility.

Keywords: DLBCL; adaptive immunity; diffuse large B-cell lymphoma; inflammation; innate immunity; prognostic index; tumor microenvironment.

Figure 1

Altered lipid metabolism and arachidonic acid (AA)-derived signaling pathways in diffuse large B-cell lymphoma (DLBCL). DLBCL is associated with decreased HDL and apoA1, impaired cholesterol efflux, and altered phospholipid composition, including reductions in PC, SM, LPC, and PE. This leads to accumulation of FFAs and decreased n-3 PUFAs. CD36-mediated uptake of oxLDL, LPS, and LCFAs activates MAPK, AKT, and STAT3 signaling, promoting glycolysis, proliferation, and EMT. Elevated intracellular AA, released by cPLA2, is metabolized via three key enzymatic routes: the COX pathway (producing PGs and TXs), the LOX pathway (yielding HETEs, LTs, and lipoxins), and the CYP450 pathway (producing EETs and HETEs). These pathways collectively contribute to inflammation, angiogenesis, and tumor progression. Explanation: ↑, increased; ↓, decreased. Abbreviations: HDL, high-density lipoprotein; LCAT, lecithin–cholesterol acyltransferase; apoA1, apolipoprotein A1; FFAs, free fatty acids; PUFAs, polyunsaturated fatty acids; oxLDL, oxidized low-density lipoprotein; LCFAs, long-chain fatty acids; LPS, lipopolysaccharide; CD36, cluster of differentiation 36; MAPK, mitogen-activated protein kinase; AKT, protein kinase B; STAT3, signal transducer and activator of transcription 3; EMT, epithelial–mesenchymal transition; LOX, lipoxygenase; 5-LOX, 5-lipoxygenase; 12,15-LOX, 12/15-lipoxygenase; 8,12,15-LOX, 8/12/15-lipoxygenase; 5-HPETE, 5-hydroperoxyeicosatetraenoic acid; 5-HETE, 5-hydroxyeicosatetraenoic acid; 8,12,15-HETE, 8,12,15-hydroxyeicosatetraenoic acid; 5-oxo ETE; 5-oxo-eicosatetraenoic acid; LTA-4, leukotriene A4; LTB-4, leukotriene B4; LTC-4, leukotriene C4; LTD-4, leukotriene D4; LTE-4, leukotriene E4; LXA-4, lipoxin A4; LXB-4, lipoxin B4; GPX-1, glutathione peroxidase 1; COX-1, cyclooxygenase 1; COX-2, cyclooxygenase 2; cPLA2, cytosolic phospholipase A2; PGH-2, prostaglandin H2; PGD-2, prostaglandin D2; PGE-2, prostaglandin E2; PGF-2, prostaglandin F2; PGI-2, prostaglandin I2; TXA-2, thromboxane A2; TXB-2, thromboxane B2; CYP-450, cytochrome P450; EETs, epoxyeicosatrienoic acids; DHETs, dihydroxyeicosatrienoic acids; 19,20-HETE, 19,20-hydroxyeicosatetraenoic acid.

Figure 2

IL-6 cytokine family signaling in the tumor microenvironment (TME). Various components of the TME, including dendritic cells, T cells, macrophages, endothelial cells, tumor-associated neutrophils (TANs), fibroblasts, and tumor cells, secrete members of the IL-6 cytokine family, such as IL-6, IL-11, IL-27, oncostatin M (OSM), leukemia inhibitory factor (LIF), IL-31, and ciliary neurotrophic factor (CNTF). These cytokines signal through specific receptor complexes that typically include glycoprotein 130 (gp130) in combination with ligand-specific receptor subunits. Ligand binding triggers the activation of canonical intracellular signaling pathways, which collectively mediate immunosuppressive functions within the TME and contribute to tumor cell survival, proliferation, and immune evasion. Explanation: ↑, increased; ↓, decreased. Abbreviations: IL-6, interleukin-6; IL-11, interleukin-11; IL-27, interleukin-27; IL-31, interleukin-31; CNTF, ciliary neurotrophic factor; OSM, oncostatin M; LIF, leukemia inhibitory factor; IL-6R, interleukin-6 receptor; IL-11R, interleukin-11 receptor; IL-27R, interleukin-27 receptor; IL-31R, interleukin-31 receptor; LIFR, leukemia inhibitory factor receptor; OSMR, oncostatin M receptor; gp130, glycoprotein 130; JAK, Janus kinase; STAT, signal transducer and activator of transcription; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTORC1, mammalian target of rapamycin complex 1; p70S6K, p70 ribosomal protein S6 kinase; Treg, regulatory T cell; Th, T helper cell; Tc, cytotoxic T cell; TAM, tumor-associated macrophage; TAN, tumor-associated neutrophil; MDSC, myeloid-derived suppressor cell; CAF, cancer-associated fibroblast; TME, tumor microenvironment; EMT, epithelial-to-mesenchymal transition.

Figure 3

Tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL). The tumor microenvironment in DLBCL is characterized by immunosuppressive signaling, enhanced angiogenesis, and impaired anti-tumor immunity. DLBCL cells express programmed cell death protein PD 1 promoting T cell exhaustion through PD-1/PD-L1 interaction. Regulatory T cells and M2 macrophages secrete IL-10, TGF-β, and VEGF, which inhibit CD4⁺, CD8⁺, and NK cells and stimulate neovascularization. TANs promote tumor invasion by releasing ROS, proteolytic enzymes, and NETs. M2 macrophages further support tumor progression, with their polarization induced by IL-4 and IL-13. Dendritic cell function is suppressed, leading to reduced T cell activation. Additionally, BCR signaling in B cells is dysregulated through activation of the NF-κB and phosphoinositide 3-PI3K/AKT pathways, contributing to immune evasion and lymphoma cell survival. Explanation: ↑, increased; ↓, decreased. Abbreviations: Abbreviations: TME, tumor microenvironment; CD36, cluster of differentiation 36; CD4, cluster of differentiation 4; CD8, cluster of differentiation 8; CD16, cluster of differentiation 16; CD32, cluster of differentiation 32; CD64, cluster of differentiation 64; CD80, cluster of differentiation 80; CD86, cluster of differentiation 86; CD163, cluster of differentiation 163; CD200R, cluster of differentiation 200 receptor; CD206, cluster of differentiation 206; CD209, cluster of differentiation 209; CD301, cluster of differentiation 301; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TIM-3, T-cell immunoglobulin and mucin-domain containing molecule 3; CTLA-4, cytotoxic T lymphocyte-associated protein 4; Treg, regulatory T cell; CD11c⁺DC, CD11c-positive dendritic cell; NK cell, natural killer cell; NETs, neutrophil extracellular traps; TAN, tumor-associated neutrophil; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; TGF-β, transforming growth factor beta; IL, interleukin; TNF-α, tumor necrosis factor alpha; CXCL12, C-X-C motif chemokine ligand 12; PI3K/AKT, Phosphoinositide 3-kinase/protein kinase B; NF-κB, Nuclear Factor kappa B; STAT3, signal transducer and activator of transcription 3; STAT6, signal transducer and activator of transcription 6; PPARγ, Peroxisome Proliferator-Activated Receptor Gamma; M-CSF, macrophage colony-stimulating factor.