High CXCR4 expression impairs rituximab response and the prognosis of R-CHOP-treated diffuse large B-cell lymphoma patients

Abstract

Survival of diffuse large B-cell lymphoma (DLBCL) patients has improved by inclusion of rituximab. Refractory/recurrent disease caused by treatment resistance is, however, a major problem. Determinants of rituximab sensitivity are not fully understood, but effect of rituximab are enhanced by antagonizing cell surface receptor CXCR4. In a two-step strategy, we tested the hypothesis that prognostic value of CXCR4 in DLBCL relates to rituximab treatment, due to a hampering effect of CXCR4 on the response of DLBCL cells to rituximab. First, by investigating the prognostic impact of CXCR4 mRNA expression separately for CHOP (n=181) and R-CHOP (n=233) cohorts and, second, by assessing the interaction between CXCR4 and rituximab in DLBCL cell lines. High CXCR4 expression level was significantly associated with poor outcome only for R-CHOP-treated patients, independent of IPI score, CD20 expression, ABC/GCB and B-cell-associated gene signature (BAGS) classifications. s. For responsive cell lines, inverse correlation was observed between rituximab sensitivity and CXCR4 surface expression, rituximab induced upregulation of surface-expressed CXCR4, and growth-inhibitory effect of rituximab increased by plerixafor, supporting negative impact of CXCR4 on rituximab function. In conclusion, CXCR4 is a promising independent prognostic marker for R-CHOP-treated DLBCL patients, possibly due to inverse correlation between CXCR4 expression and rituximab sensitivity.

Genetic alterations in B cell lymphoma subtypes as potential biomarkers for non-invasive diagnosis, prognosis, therapy, and disease monitoring

“…Yuan et al showed that high microRNA-125b and microRNA-130a levels in the serum of DLBCL cases are associated with R-CHOP resistance in DLBCL cases (Yuan et al, 2016). Laursen et al showed that high expression of CXCR4 on the tumor cell surface may be responsible for R-CHOP resistance in a subset of DLBCL cases (Laursen et al, 2019). Another study by Wilson et al asked whether ABC DLBCL patients who have chemotherapy refractory disease can be treated through inhibition of BCR signaling.…”

OSdlbcl: An online consensus survival analysis web server based on gene expression profiles of diffuse large B‐cell lymphoma

“…Independent validation across different cohorts is of great importance for biomarker development, and OSdlbcl is a web server that could facilitate the cross‐validation of the prognostic value of biomarkers across seven DLBCL cohorts. To determine the prognosis performance of OSdlbcl, we collected 23 previously published DLBCL prognostic factors at the mRNA or protein level and tested their prognostic power in OSdlbcl at the mRNA level (Table , Figure ) . The forest plots more effectively presented the comparison results from references and OSdlbcl (Figure ).…”

“…To determine the prognosis performance of OSdlbcl, we collected 23 previously published DLBCL prognostic factors at the mRNA or protein level and tested their prognostic power in OSdlbcl at the mRNA level (Table 2, Figure 1). 2,9,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] The forest plots more effectively presented the comparison results from references and OSdlbcl ( Figure S1). Results showed that about 52% (12 out of 23) of biomarkers have significant prognostic values in the combined cohorts, while the remaining biomarkers (11 out of 23) present significant prognostic values in one or more cohorts ( Table 2).…”

The CXCR4-CXCL12-Axis is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects in Vitro

“…For all three genes, their implication in cancer surveillance has been demonstrated in more than 20 different solid cancer types [7][8][9]. Their role has also been investigated in DLBCL [10][11][12][13][14][15][16], however, these data are inconsistent and rather limited. We observed CXCR4 expression in non-neoplastic GC-B but a significantly higher expression in DLBCL.…”

“…In solid cancer, abnormalities in the CXCR4-CXCL12-axis have been linked to many processes, including proliferation, survival, migration, invasion, and metastasis in solid cancer [7][8][9], thereby providing evidence for the importance of this chemokine signalling pathway in these malignancies. So far, we and other groups performed studies investigating the role of CXCR4 in DLBCL, whereby results mainly point towards a prominent role of CXCR4 in lymphoma dissemination [10][11][12][13][14][15][16]. However, data from these studies are to some extent inconsistent and limited.…”