Tumor Microenvironment and Immunotherapy-Based Approaches in Mantle Cell Lymphoma.
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ABSTRACT:
SUBMITTER: Saleh K
PROVIDER: S-EPMC9265015 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a heterogeneous clinical and biological behavior. SOX11 oncogenic expression contributes to the aggressiveness of these tumors by different mechanisms, including tumor and stromal cell interactions. However, the precise composition of the immune cell microenvironment of MCL, its possible relationship to SOX11 expression, and how it may contribute to tumor behavior is not well known. Here, we performed an integrative transcriptome analysis of 730 immune-related genes combined with the immune cell phenotype analysis by immunohistochemistry in SOX11+ and SOX11- primary nodal MCL cases and non-neoplastic reactive lymph nodes. SOX11+ MCL had a significant lower T-cell intratumoral infiltration compared with negative cases. A reduced expression of MHCI/II-like and T-cell costimulation and signaling activation related transcripts was significantly associated with poor clinical outcome. Moreover, we identified CD70 as a SOX11 direct target gene, whose overexpression was induced in SOX11+, but not SOX11- tumor cells by CD40L in vitro. CD70 was overexpressed in primary SOX11+ MCL and it was associated with an immune unbalance of the tumor microenvironment characterized by increased number of effector regulatory t (Treg) cell infiltration, higher proliferation, and aggressive clinical course. CD27 was expressed with moderate to strong intensity in 76% of cases. Overall, our results suggest that SOX11 expression in MCL is associated with an immunosuppressive microenvironment characterized by CD70 overexpression in tumor cells, increased Treg cell infiltration and downmodulation of antigen processing, and presentation and T-cell activation that could promote MCL progression and represent a potential target for tailored therapies.
| S-EPMC8641098 | biostudies-literature
Project description:Mantle cell lymphoma (MCL) is a set of heterogeneous non-Hodgkin lymphoma characterized by involvement of lymph nodes, spleen, bone marrow and blood. Under conventional treatment, survival time is 4 to 5 years with short remission period and there is still no standard treatment for MCL. In general, a close observation period called "watchful waiting" is used in elderly patients with low-risk slow clinical progress. And intensive chemotherapy including high-dose of cytarabine ± autologous hematopoietic stem cell transplantation (auto-HSCT) is recommended for younger and fit patients. Allogenic stem cell transplantation (allo-SCT) and drugs targeting the cell metabolic pathway, such as bortezomib (NF-?B inhibitor) and lenalidomide (anti-angiogenesis drug), are considerable treatments for relapsed/refractory patients. Clinical trials and less intensive chemotherapy such as R-CHOP (rituximab with cyclophosphamide, hydroxydaunomycin, oncovin and prednisone) and R-bendamustine should be considered for elderly MCL patients who are at intermediate/high risk. Recent clinical trials with ibrutinib (Bruton's Tyrosine Kinase inhibitor) and temsirolimus (mTOR inhibitor) have shown excellent efficacies in the treatment of MCL. This review will introduce the present status and major therapeutic progress in the treatment of MCL over recent years in order to provide a cutting edge to look into promising clinical progress of MCL.
| S-EPMC4923656 | biostudies-literature
Project description: Not available
| S-EPMC10567800 | biostudies-literature
Project description:Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma frequently involved in the lymph nodes, bone marrow, spleen, and gastrointestinal tract. We examined the role of IL-6 in MCL. Human MCL cells expressed the membrane gp130 and soluble gp80, and some of them also secreted IL-6. Neutralizing autocrine IL-6 and/or blocking IL-6 receptors in IL-6(+)/gp80(+) MCL cells inhibited cell growth, enhanced the rate of spontaneous apoptosis, and increased sensitivity to chemotherapy drugs. For IL-6(-) or gp80(low) MCL cells, paracrine or exogenous IL-6 or gp80 protected the cells from stress-induced death. Knockdown of gp80 in gp80(high) MCL cells rendered the cells more sensitive to chemotherapy drugs, even in the presence of exogenous IL-6. In contrast, overexpression of gp80 in gp80(low)/IL-6(+) MCL cells protected the cells from chemotherapy drug-induced apoptosis in vitro and compromised the therapeutic effect of chemotherapy in vivo. IL-6 activated the Jak2/STAT3 and PI3K/Akt pathways in MCL, and the inhibition of these pathways completely or partially abrogated IL-6-mediated protection of MCL cells. Hence, our study identifies IL-6 as a key cytokine for MCL growth and survival and suggests that targeting the IL-6 pathway may be a novel way to improve the efficacy of chemotherapy in MCL patients.
| S-EPMC3488890 | biostudies-other
Project description:Classical MCL (cMCL) constitutes 6-8% of all B cell NHL. Despite recent advances, MCL is incurable except with allogeneic stem cell transplant. Blastic mantle cell lymphoma (bMCL) is a rarer subtype of cMCL associated with an aggressive clinical course and poor treatment response, frequent relapse and poor outcomes. We treated 13 bMCL patients with combined epigenetic and immunotherapy treatment consisting of vorinostat, cladribine and rituximab (SCR). We report an increased OS greater than 40 months with several patients maintaining durable remissions without relapse for longer than 5 years. This is remarkably better then current treatment regimens which in bMCL range from 14.5-24 months with conventional chemotherapy regimens. We demonstrate that the G/A870 CCND1 polymorphism is predictive of blastic disease, nuclear localization of cyclinD1 and response to SCR therapy. The major resistance mechanisms to SCR therapy are loss of CD20 expression and evasion of treatment by sanctuary in the CNS. These data indicate that administration of epigenetic agents improves efficacy of anti-CD20 immunotherapies. This approach is promising in the treatment of MCL and potentially other previously treatment refractory cancers.
| S-EPMC9450988 | biostudies-literature
Project description:BackgroundThere is evidence to consider that the tumor microenvironment (TME) composition associates with antitumor immune response, and may predict the outcome of various non-Hodgkin lymphoma subtypes. However, in the case of mantle cell lymphoma (MCL), a rare and aggressive disease, there is lacking a detailed study of the TME components, as well as an integrative approach among them in patients' samples. Also, from the genetic point of view, it is known that single nucleotide variants (SNVs) in immune-response genes are among important regulators of immunity. At present, it is uncertain whether SNVs in candidate immune-response genes and the TME composition are able to alter the prognosis in MCL.MethodsWe assessed a detailed TME composition in 88 MCL biopsies using immunohistochemistry, which was automatically analyzed by pixel counting (Aperio system). We also genotyped SNVs located in candidate immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, IL17F) in 95 MCL patients. We tested whether the SNVs could modulate the respective protein expression and TME composition in the tumor compartment. Finally, we proposed survival models in rituximab-treated patients, considering immunohistochemical and SNV models.ResultsHigh FOXP3/CD3 ratios (p =?0.001), high IL17A levels (p =?0.003) and low IL2 levels (p =?0.03) were individual immunohistochemical predictors of poorer survival. A principal component, comprising high quantities of macrophages and high Ki-67 index, also worsened outcome (p =?0.02). In the SNV model, the CC haplotype of IL10 (p <?0.01), the GG genotype of IL2 rs2069762 (p?=?0.02) and the AA+AG genotypes of TGFBR2 rs3087465 (p <?0.01) were independent predictors of outcome. Finally, the GG genotype of TGFB1 rs6957 associated with lower tumor TGF? levels (p =?0.03) and less CD163+ macrophages (p =?0.01), but did not modulate patients' survival.ConclusionsOur results indicate that the TME composition has relevant biological roles in MCL. In this setting, immunohistochemical detection of T-reg cells, IL17A and IL2, coupled with SNV genotyping in IL10, TGFBR2 and IL2, may represent novel prognostic factors in this disease, following future validations.
| S-EPMC7919095 | biostudies-literature
Project description:BackgroundMantle cell lymphoma (MCL) remains incurable using conventional chemotherapeutic approaches. New clinical data show that some patients have a chronic/indolent course and others have a more fulminant course and short survival, similar to that of patients with acute leukemias.MethodsThis review presents an overview of this aggressive disease, including the diagnosis, epidemiology, prognosis, and management of this protean and challenging condition.ResultsDistinguishing indolent MCL from in situ MCL is important but can be challenging. Molecular exploration has identified SOX11 and HDAC11 as potential candidate genes for discrimination of indolent cases. Improvements in the prognosis in MCL are likely the result of earlier identification of more indolent cases and the application of modern modalities, including rituximab and autologous transplantation. Younger patients may be able to tolerate more intensive therapy, while treatment for elderly or frail patients may focus on maintenance to prolong remission. For patients with relapsed disease, some agents have shown promise, such as lenalidomide and bortezomib. Emerging drugs such as PCI37625 and CAL-101 are being explored in phase I and II studies.ConclusionsAlthough patients with MCL continue to experience poor outcomes, new treatment approaches for various stages of disease are showing promise in improving survival.
| S-EPMC4015063 | biostudies-literature
Project description:Mantle cell lymphoma (MCL) is biologically and clinically heterogeneous and would benefit from prognostic biomarkers to guide management. Circulating tumor DNA (ctDNA) is a novel prognostic biomarker in diffuse large B-cell lymphoma that may have applicability in MCL. We analyzed ctDNA dynamics in previously untreated patients with MCL who received induction therapy with bortezomib and DA-EPOCH-R for 6 cycles followed by random assignment to observation or bortezomib maintenance in responding patients in a prospective phase 2 study. Most patients also underwent initial treatment window of bortezomib alone prior to induction. Serum was collected pretreatment, after the window, after cycles 1 and 2, at the end of induction, and at each follow-up visit along with restaging computed tomography scans. Next-generation sequencing was used to identify and quantify ctDNA encoding the immunoglobulin receptor sequences in serum as markers of minimal residual disease. Fifty-three patients were enrolled, with a median follow-up of 12.7 years. Patients without detectable ctDNA after 2 cycles of induction had longer progression-free survival (PFS) and overall survival (OS) compared with those with detectable ctDNA (median PFS, 2.7 vs 1.8 years; overall P = .005; median OS, 13.8 vs 7.4 years; overall P = .03). Notably, in vivo assessment of ctDNA dynamics during the bortezomib window was not prognostic, and there was no difference in PFS or OS with bortezomib maintenance. ctDNA monitoring after induction showed that molecular relapse preceded clinical relapse in some cases. In conclusion, interim ctDNA negativity strongly correlates with improved survival and supports the investigation of response-adapted strategies. This trial was registered at www.clinicaltrials.gov as #NCT00114738.
| S-EPMC9043939 | biostudies-literature
Project description:A dominant paradigm being developed in immunotherapy for hematologic malignancies is of adaptive immunotherapy that involves chimeric antigen receptor (CAR) T cells and bispecific T-cell engagers. CAR T-cell therapy has yielded results that surpass those of the existing salvage immunochemotherapy for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after first-line immunochemotherapy, while offering a therapeutic option for patients with follicular lymphoma (FL) and mantle cell lymphoma (MCL). However, the role of the innate immune system has been shown to prolong CAR T-cell persistence. Cluster of differentiation (CD) 47-blocking antibodies, which are a promising therapeutic armamentarium for DLBCL, are novel innate immune checkpoint inhibitors that allow macrophages to phagocytose tumor cells. Intratumoral Toll-like receptor 9 agonist CpG oligodeoxynucleotide plays a pivotal role in FL, and vaccination may be required in MCL. Additionally, local stimulator of interferon gene agonists, which induce a systemic anti-lymphoma CD8+ T-cell response, and the costimulatory molecule 4-1BB/CD137 or OX40/CD134 agonistic antibodies represent attractive agents for dendritic cell activations, which subsequently, facilitates initiation of productive T-cell priming and NK cells. This review describes the exploitation of approaches that trigger innate immune activation for adaptive immune cells to operate maximally in the tumor microenvironment of these lymphomas.
| S-EPMC8750340 | biostudies-literature
Project description:The CD38 antigen is expressed in several hematological malignancies, and the anti-CD38 monoclonal antibodies Daratumumab and Isatuximab have an established role in the therapy of multiple myeloma. However, data on the therapeutic utility of CD38 targeting in other lymphoid malignancies are limited. In chronic lymphocytic leukemia, the prognostic significance of CD38 expression is well accepted, and preclinical studies on the use of Daratumumab in monotherapy or combination therapy have demonstrated considerable efficacy. In other lymphoproliferative disorders, preclinical and clinical data have not been as compelling; however, CD38 overexpression likely contributes to resistance to checkpoint inhibitors, prompting numerous clinical trials in Hodgkin and non-Hodgkin lymphoma to investigate whether blocking CD38 enhances the efficacy of checkpoint inhibitors. Furthermore, due to its widespread expression in hematological tumors, CD38 represents an attractive target for cellular therapies such as CAR-T cells. The present review discusses current knowledge of CD38 expression and its implications in various lymphoid malignancies. Furthermore, it addresses current and future therapeutic perspectives, with a particular emphasis on the significance of CD38 interaction with immune cells of the tumor microenvironment. Lastly, results of ongoing studies using anti-CD38 antibodies will be reviewed.
| S-EPMC7226059 | biostudies-literature