Expression of CD40 is a positive prognostic factor of diffuse large B-cell lymphoma treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)

Song, Guoqi; Ni, Huiyun; Zou, Lin; Wang, Shukui; Tian, Fuliang; Hong, Liu; Cho, William C.

doi:10.2147/ott.s96992

Cited by 6 publications

(4 citation statements)

References 30 publications

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“…Findings on CD40 are consistent with the results published by Keidai et al, in which 51.9% of NSCLC tissue specimens [24] and 78% of lung cancer cell lines (14 of 18) expressed CD40 [25]. Furthermore, the expression of CD40 has been documented in many other carcinomas, such as melanomas [26], hepatocellular carcinomas [27] thyroid [28], bladder [29], colon [30], esophageal squamous cell [31], ovarian [32], gastric [33], cervical [34], breast and pancreatic cancer [35], as well as in the vast majority of hematological malignancies [36,37].…”

Section: Discussionmentioning

confidence: 99%

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients

Dimitrakopoulos

Κοττόρου

Antonacopoulou

et al. 2019

JCM

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An increasing number of studies implicates the NF-κB (Nuclear Factor of kappa light chain gene enhancer in B cells) alternative pathway in non-small-cell lung cancer (NSCLC). We assessed the clinical significance of CD40 (Tumor necrosis factor receptor superfamily member 5, TNFRSF5), BAFFR (B-cell activating factor receptor), RANK (Receptor activator of NF-κB) and LTβR (lymphotoxin β receptor) receptors, which activate the alternative pathway of NF-κB, in NSCLC. Evaluation of CD40, BAFFR, RANK and LTβR expression was performed based on the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, while protein expression was assessed by immunohistochemistry in specimens from 119 operated NSCLC patients. CD40 gene overexpression was correlated with improved five-year overall survival (OS) (p < 0.001), while increased BAFFR and LTβR mRNA levels were associated with worse OS in patients with adenocarcinomas (p < 0.001 and p < 0.001, respectively). Similarly, patients with adenocarcinomas exhibited a negative correlation between membranous BAFFR protein expression in carcinoma cells and three- and five-year survival (p = 0.021; HR, 4.977 and p = 0.030; HR, 3.358, respectively) as well as between BAFFR protein overexpression in cancer-associated fibroblasts (CAFs) and two-year survival (p = 0.036; HR, 1.983). Patients with increased LTβR nuclear protein staining or stage II patients with lower cytoplasmic LTβR protein expression had worse five-year OS (p = 0.039 and p = 0.008, respectively). Moreover, CD40 protein expression in tumor infiltrating lymphocytes (TILs) and CAFs was positively associated with metastatic spread while BAFFR protein expression in CAFs was negatively associated with bone metastasis (p = 0.041). Our data suggests that CD40, BAFFR, RANK and LTβR play an important role in NSCLC and further supports the role of NF-κB alternative pathway in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients

Dimitrakopoulos

Κοττόρου

Antonacopoulou

et al. 2019

JCM

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“…It remains to be seen if this new technology will be widely accepted in lymphoma centers worldwide. In addition to COO classification, immunohistochemical (IHC) studies have identified multiple protein markers, such as CD5, Ki-67, FOXP1, HLA-I, p21, and CD40, that prospectively showed prognostic value for R-CHOP-treated DLBCL [ 13 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

Mutations of CREBBP and SOCS1 are independent prognostic factors in diffuse large B cell lymphoma: mutational analysis of the SAKK 38/07 prospective clinical trial cohort

et al. 2017

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Background/purposeRecently, the mutational background of diffuse large B cell lymphoma (DLBCL) has been revealed, identifying specific genetic events that drive lymphomagenesis. However, the prognostic value of these mutations remains to be determined. Prognostic biomarkers in DLBCL are urgently needed, since the current clinical parameter-based factors (e.g., International Prognostic Index (IPI)) are insufficient, particularly in identifying patients with poor prognosis who might benefit from alternative treatments.MethodsWe investigated the prognostic value of somatic mutations in DLBCL in a clinical trial (NCT00544219) patient cohort homogenously treated with six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP), followed by two cycles of R (R-CHOP-14). The primary endpoint was event-free survival (EFS) at 2 years. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Targeted high-throughput sequencing (HTS) of tumor genomic DNA was performed on all exons or hotspots of 68 genes frequently mutated in B cell lymphomas. Mutational data was correlated with the endpoints to identify prognostic associations.ResultsTargeted HTS detected somatic mutations in 71/76 (93%) of investigated cases. The most frequently mutated genes were KMT2D, SOCS1, GNA13, and B2M. Survival analysis revealed that CREBBP- and EP300-mutated cases had significantly worse OS, PFS, and EFS. In addition, ATM mutations predicted worse outcomes for all three clinical endpoints in germinal center B cell-like DLBCL. In contrast, SOCS1 mutations were associated with better PFS. On multivariable analysis taken into account IPI and failure to achieve complete remission, CREBBP and EP300 mutations remained significant to predict worse OS, PFS, and EFS.ConclusionTargeted mutation analysis of a uniformly treated prospective clinical trial DLBCL cohort identifies tumor-based genetic prognostic markers that could be useful in the clinical management of such patients.Trial registrationClinicalTrials.gov NCT00544219Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0438-7) contains supplementary material, which is available to authorized users.

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“…54 An active CD40 signaling pathway was found to be predictive of treatment response in a phase I trial of dacetuzumab, a CD40-specific antibody with partial agonistic activity 56 and CD40 expression has generally emerged as a favorable prognostic marker in patients on CHOP or R-CHOP. [58][59][60] Our experimental data do not completely rule out tumor-cell extrinsic effects of CD40 targeting, but the comparable levels of tumor reduction in WT and RAGγc -/mice suggest that direct killing by CD40 activation is the dominant mechanism of tumor control in our model.…”

Section: Discussionmentioning

confidence: 66%

Treg-selective IL-2 starvation synergizes with CD40 activation to sustain durable responses in lymphoma models

Stirm

Leary

Wüst

et al. 2023

J Immunother Cancer

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BackgroundRoughly half of all diffuse large B-cell lymphomas (DLBCLs) are infiltrated by large numbers of regulatory T-cells (Tregs). Although the presence of ‘effector’ Tregs in particular is associated with an inferior prognosis in patients on standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy, the role of this cell type during lymphoma initiation and progression is poorly understood.MethodsHere, we use tissue microarrays containing prospectively collected DLBCL patient specimens, as well as data from publicly available cohorts to explore the mutational landscape of Treg-infiltrated DLBCL. We further take advantage of a model of MYC-driven lymphoma to mechanistically dissect the contribution of Tregs to lymphoma pathogenesis and to develop a strategy of Treg-selective interleukin-2 (IL-2) starvation to improve immune control of MYC-driven lymphoma.ResultsWe find that all genetic DLBCL subtypes, except for one characterized by co-occurringMYD88/CD79mutations, are heavily infiltrated by Tregs. Spectral flow cytometry and scRNA-sequencing reveal the robust expression of functional and immunosuppressive markers on Tregs infiltrating MYC-driven lymphomas; notably, we find that intratumoral Tregs arise due to local conversion from naïve CD4+precursors on tumor contact. Treg ablation in Foxp3iDTRmice, or by antibody-mediated Treg-selective blockade of IL-2 signaling, strongly reduces the lymphoma burden. We identify lymphoma B-cells as a major source of IL-2, and show that the effects of Treg depletion are reversed by the simultaneous depletion of Foxp3-negative CD4+T-cells, but not CD8+T-cells or natural killer (NK) cells. The inhibition of ATP hydrolyzation and adenosine production by Tregs at least partly phenocopies the effects of Treg depletion. Treg depletion further synergizes with pro-apoptotic CD40 activation to sustain durable responses.ConclusionThe combined data implicate Tregs as a potential therapeutic target in DLBCL, especially in combination with other immunotherapies.

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Expression of CD40 is a positive prognostic factor of diffuse large B-cell lymphoma treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)

Cited by 6 publications

References 30 publications

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients

Mutations of CREBBP and SOCS1 are independent prognostic factors in diffuse large B cell lymphoma: mutational analysis of the SAKK 38/07 prospective clinical trial cohort

Treg-selective IL-2 starvation synergizes with CD40 activation to sustain durable responses in lymphoma models

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