R-CHOP resistance in diffuse large B-cell lymphoma: biological and molecular mechanisms

Abstract

Although the first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone regimen (R-CHOP) substantially improved outcomes for patients with diffuse large B-cell lymphoma (DLBCL), 40% of the patients suffered from relapsed/refractory disease and had poor survival outcomes. The detailed mechanism underlying R-CHOP resistance has not been well defined. For this review, we conducted a thorough search for literature and clinical trials involving DLBCL resistance. We discussed DLBCL biology, epigenetics, and aberrant signaling of the B-cell receptor (BCR), phosphatidylinositol 3-kinase (PI3K)/Akt, nuclear factor kappa light chain enhancer of activated B-cells (NF-κB), and the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways as defining mechanisms of DLBCL heterogeneity and R-CHOP resistance. The cell of origin, double- or triple-hit lymphoma and double-protein-expression, clonal evolution, tumor microenvironment, and multi-drug resistance help to contextualize DLBCL resistance in an (epi)genetically and biologically comparative manner. With better understanding of the biological and molecular landscape of DLBCL, a more detailed classification system and tailored treatments will ideally become available to further improve the prognosis of DLBCL patients.

Figure 1

R-CHOP-resistant DLBCL microenvironment. This is the schematic representation of the defining features in the tumor microenvironment of DLBCL. The tumor microenvironment contains immune cells, stromal cells, and extracellular components (eg, matrix, chemokines, cytokines, exosomes, and blood vessels). Stromal cells of the tumor microenvironment include mesenchymal stromal cells, lymphoma-associated macrophages, myeloid-derived suppressor cells, and dendritic cells. Immune cells of the DLBCL microenvironment include cytotoxic T cells, follicular dendritic cells, regulatory T cells, natural killer cells, macrophages, and reticulum cells, which are essential for the multiple cycles of B-cell proliferation, mutation, selection, and immune evasion. The response to R-CHOP is affected by the tumor microenvironment in terms of cell adhesion to the stromal cells, angiogenesis, multi-drug resistance upregulation, and immune evasion. ABCG-2: ATP binding cassette subfamily G member 2; ENO-1: Enolase 1; CAM-DR: Cell adhesion-mediated drug resistance; CAR-T: Chimeric antigen receptor-T cell; DLBCL: Diffuse large B cell lymphoma; P-gp: P-glycoprotein; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; R-CHOP: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

Figure 2

Targeting molecular pathways in R-CHOP-resistant DLBCL. This is the schematic representation of the BCR, PI3K-Akt, NF-κB, and JAK-STAT3 molecular signaling pathways in DLBCL. Aberrant expression of these pathways have emerged as top candidate targets implicated in R-CHOP resistance. These abnormalities are partially elucidated by epigenetic abnormalities. BCR: B cell receptor; BTK: Bruton's tyrosine kinase; CARD11: Caspase-associated recruitment domain 11; DLBCL: Diffuse large B cell lymphoma; EZH2: Enhancer of zeste 2; FOXO: Forkhead box O; HDAC: Histone deacetylase; JAK-STAT3: Janus kinase/signal transducer and activator of transcription 3; MALT-1: Mucosa-associated lymphoid tissue lymphoma translocation-1; MAPK: Mitogen-activated protein kinase; NEMO: NF-kappa B essential modulator; NF-κB: Nuclear factor kappa light chain enhancer of activated B cells; PI3K-Akt: Phosphatidylinositol 3-kinase/Akt; PKCβ: Protein kinase C β; PTEN: Phosphatase and tensin homolog; PDK-1: Phosphatidylinositol-dependent kinase 1; PRDM1: Positive regulatory domain containing 1; R-CHOP: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; SYK: Spleen tyrosine kinase; SFK: Src family of protein tyrosine kinases; IRAK: Interleukin 1 receptor associated kinase.