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The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 52422

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Prof. Dr. Silvia Deaglio

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Guest Editor

Department of Medical Sciences, University of Turin, 10126 Turin, Italy
Interests: tumor microenvironment; tumor metabolism; cancer immune suppression; chronic lymphoid malignancies; patient-derived xenografts

PD Dr. Tanja Nicole Hartmann

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Guest Editor

Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine and Medical Center, University of Freiburg, Breisacher Str. 117, 79106 Freiburg, Germany
Interests: tumor microenvironment; tumor cell trafficking and organ infiltration; adhesion; integrin; chronic lymphocytic leukemia; acute myeloid leukemia

Special Issue Information

Dear colleagues,

Therapy for patients with B cell malignancies is rapidly evolving from chemoimmunotherapy-based regimens to drugs that inhibit kinase signaling or induce apoptosis. Although these approaches are often successful in controlling the disease for a long time, in most cases they are unable to cure the disease, underlining the need for combination strategies.

The tumor microenvironment is a particular environment where cancer cells reside and find optimal conditions to survive, resist therapies, and eventually progress. Being composed of soluble factors, accessory cells, and an extracellular matrix, it is a complex niche of supportive cell–cell communication. The niche is shaped by the tumor cells towards decreased oxygen levels, decreased nutrients, and local acidosis, all circumstances that contribute to make cells of the immune system unable to attack cancer cells, transforming them into tumor supporters.

This collection hosts review articles from scientists that have been studying the composition of the tumor microenvironment in adult B cell leukemias and lymphomas, with a translational perspective.

Prof. Silvia Deaglio
PD Dr. Tanja Nicole Hartmann
Guest Editors

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Keywords

B-cell malignancies
Tumor microenvironment
Immune suppression
Adhesion
Homing
Metabolic adaptation
Hypoxia

Published Papers (11 papers)

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Editorial

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2 pages, 162 KiB

Open AccessEditorial

The Importance of Tumor–Host Interactions in Adult B-Cell Leukemias and Lymphomas

by Silvia Deaglio and Tanja Nicole Hartmann

Int. J. Mol. Sci. 2020, 21(18), 6915; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186915 - 21 Sep 2020

Cited by 1 | Viewed by 1254

Abstract

The tumor microenvironment plays a crucial role in driving the behavior and the aggressiveness of neoplastic cells [...] Full article

(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)

Research

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17 pages, 3520 KiB

Open AccessArticle

Optimized Xenograft Protocol for Chronic Lymphocytic Leukemia Results in High Engraftment Efficiency for All CLL Subgroups

by Sarah Decker, Anabel Zwick, Shifa Khaja Saleem, Sandra Kissel, Andres Rettig, Konrad Aumann and Christine Dierks

Int. J. Mol. Sci. 2019, 20(24), 6277; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246277 - 12 Dec 2019

Cited by 7 | Viewed by 3775

Abstract

Preclinical drug development for human chronic lymphocytic leukemia (CLL) requires robust xenograft models recapitulating the entire spectrum of the disease, including all prognostic subgroups. Current CLL xenograft models are hampered by inefficient engraftment of good prognostic CLLs, overgrowth with co-transplanted T cells, and the need for allogeneic humanization or irradiation. Therefore, we aimed to establish an effective and reproducible xenograft protocol which allows engraftment of all CLL subtypes without the need of humanization or irradiation. Unmanipulated NOD.Cg-Prkdc^scidIl2rg^tm1Sug/JicTac (NOG) mice in contrast to C.Cg-Rag2^tm1Fwa-/-Il2rg^tm1Sug/JicTac (BRG) mice allowed engraftment of all tested CLL subgroups with 100% success rate, if CLL cells were fresh, injected simultaneously intra-peritoneally and intravenously, and co-transferred with low fractions of autologous T cells (2%–4%). CLL transplanted NOG mice (24 different patients) developed CLL pseudofollicles in the spleen, which increased over 4–6 weeks, and were then limited by the expanding autologous T cells. Ibrutinib treatment studies were performed to validate our model, and recapitulated treatment responses seen in patients. In conclusion, we developed an easy-to-use CLL xenograft protocol which allows reliable engraftment for all CLL subgroups without humanization or irradiation of mice. This protocol can be widely used to study CLL biology and to explore novel drug candidates. Full article

(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)

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18 pages, 1854 KiB

Open AccessArticle

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

by Katrin Pansy, Julia Feichtinger, Barbara Ehall, Barbara Uhl, Miriam Sedej, David Roula, Beata Pursche, Axel Wolf, Manuel Zoidl, Elisabeth Steinbauer, Verena Gruber, Hildegard T Greinix, Katharina T. Prochazka, Gerhard G. Thallinger, Akos Heinemann, Christine Beham-Schmid, Peter Neumeister, Tanja M. Wrodnigg, Karoline Fechter and Alexander JA. Deutsch

Int. J. Mol. Sci. 2019, 20(19), 4740; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194740 - 24 Sep 2019

Cited by 14 | Viewed by 3916

Abstract

In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas. Full article

(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)

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Review

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19 pages, 1001 KiB

Open AccessReview

The Interplay between MicroRNAs and the Components of the Tumor Microenvironment in B-Cell Malignancies

by Sherien M. El-Daly, Recep Bayraktar, Simone Anfossi and George A. Calin

Int. J. Mol. Sci. 2020, 21(9), 3387; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093387 - 11 May 2020

Cited by 19 | Viewed by 4764

Abstract

An increased focus is being placed on the tumorigenesis and contexture of tumor microenvironment in hematopoietic and solid tumors. Despite recent clinical revolutions in adoptive T-cell transfer approaches and immune checkpoint blockade, tumor microenvironment is a major obstacle to tumor regression in B-cell malignancies. A transcriptional alteration of coding and non-coding RNAs, such as microRNAs (miRNAs), has been widely demonstrated in the tumor microenvironment of B-cell malignancies. MiRNAs have been associated with different clinical-biological forms of B-cell malignancies and involved in the regulation of B lymphocyte development, maturation, and function, including B-cell activation and malignant transformation. Additionally, tumor-secreted extracellular vesicles regulate recipient cell functions in the tumor microenvironment to facilitate metastasis and progression by delivering miRNA contents to neighboring cells. Herein, we focus on the interplay between miRNAs and tumor microenvironment components in the different B-cell malignancies and its impact on diagnosis, proliferation, and involvement in treatment resistance. Full article

(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)

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16 pages, 1381 KiB

Open AccessReview

VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects

by Andrea Härzschel, Antonella Zucchetto, Valter Gattei and Tanja Nicole Hartmann

Int. J. Mol. Sci. 2020, 21(6), 2206; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062206 - 23 Mar 2020

Cited by 19 | Viewed by 5886

Abstract

Lineage commitment and differentiation of hematopoietic cells takes place in well-defined microenvironmental surroundings. Communication with other cell types is a vital prerequisite for the normal functions of the immune system, while disturbances in this communication support the development and progression of neoplastic disease. Integrins such as the integrin very late antigen-4 (VLA-4; CD49d/CD29) control the localization of healthy as well as malignant B cells within the tissue, and thus determine the patterns of organ infiltration. Malignant B cells retain some key characteristics of their normal counterparts, with B cell receptor (BCR) signaling and integrin-mediated adhesion being essential mediators of tumor cell homing, survival and proliferation. It is thus not surprising that targeting the BCR pathway using small molecule inhibitors has proved highly effective in the treatment of B cell malignancies. Attenuation of BCR-dependent lymphoma–microenvironment interactions was, in this regard, described as a main mechanism critically contributing to the efficacy of these agents. Here, we review the contribution of VLA-4 to normal B cell differentiation on the one hand, and to the pathophysiology of B cell malignancies on the other hand. We describe its impact as a prognostic marker, its interplay with BCR signaling and its predictive role for novel BCR-targeting therapies, in chronic lymphocytic leukemia and beyond. Full article

(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)

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22 pages, 1007 KiB

Open AccessReview

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

by Francesca Arruga, Benjamin Baffour Gyau, Andrea Iannello, Nicoletta Vitale, Tiziana Vaisitti and Silvia Deaglio

Int. J. Mol. Sci. 2020, 21(5), 1825; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051825 - 06 Mar 2020

Cited by 74 | Viewed by 6912

Abstract

Representing the major cause of morbidity and mortality for chronic lymphocytic leukemia (CLL) patients, immunosuppression is a common feature of the disease. Effectors of the innate and the adaptive immune response show marked dysfunction and skewing towards the generation of a tolerant environment that favors disease expansion. Major deregulations are found in the T lymphocyte compartment, with inhibition of CD8⁺ cytotoxic and CD4⁺ activated effector T cells, replaced by exhausted and more tolerogenic subsets. Likewise, differentiation of monocytes towards a suppressive M2-like phenotype is induced at the expense of pro-inflammatory sub-populations. Thanks to their B-regulatory phenotype, leukemic cells play a central role in driving immunosuppression, progressively inhibiting immune responses. A number of signaling cascades triggered by soluble mediators and cell–cell contacts contribute to immunomodulation in CLL, fostered also by local environmental conditions, such as hypoxia and derived metabolic acidosis. Specifically, molecular pathways modulating T-cell activity in CLL, spanning from the best known cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) to the emerging T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT)/CD155 axes, are attracting increasing research interest and therapeutic relevance also in the CLL field. On the other hand, in the microenvironment, the B cell receptor (BCR), which is undoubtedly the master regulator of leukemic cell behavior, plays an important role in orchestrating immune responses, as well. Lastly, local conditions of hypoxia, typical of the lymphoid niche, have major effects both on CLL cells and on non-leukemic immune cells, partly mediated through adenosine signaling, for which novel specific inhibitors are currently under development. In summary, this review will provide an overview of the molecular and microenvironmental mechanisms that modify innate and adaptive immune responses of CLL patients, focusing attention on those that may have therapeutic implications. Full article

(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)

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14 pages, 1375 KiB

Open AccessReview

Bone Marrow Stromal Cells Drive Key Hallmarks of B Cell Malignancies

by Maurizio Mangolini and Ingo Ringshausen

Int. J. Mol. Sci. 2020, 21(4), 1466; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041466 - 21 Feb 2020

Cited by 19 | Viewed by 4775

Abstract

All B cell leukaemias and a substantial fraction of lymphomas display a natural niche residency in the bone marrow. While the bone marrow compartment may only be one of several sites of disease manifestations, the strong clinical significance of minimal residual disease (MRD) in the bone marrow strongly suggests that privileged niches exist in this anatomical site favouring central elements of malignant transformation. Here, the co-existence of two hierarchical systems, originating from haematopoietic and mesenchymal stem cells, has extensively been characterised with regard to regulation of the former (blood production) by the latter. How these two systems cooperate under pathological conditions is far less understood and is the focus of many current investigations. More recent single-cell sequencing techniques have now identified an unappreciated cellular heterogeneity of the bone marrow microenvironment. How each of these cell subtypes interact with each other and regulate normal and malignant haematopoiesis remains to be investigated. Here we review the evidences of how bone marrow stroma cells and malignant B cells reciprocally interact. Evidently from published data, these cell–cell interactions induce profound changes in signalling, gene expression and metabolic adaptations. While the past research has largely focussed on understanding changes imposed by stroma- on tumour cells, it is now clear that tumour-cell contact also has fundamental ramifications for the biology of stroma cells. Their careful characterisations are not only interesting from a scientific biological viewpoint but also relevant to clinical practice: Since tumour cells heavily depend on stroma cells for cell survival, proliferation and dissemination, interference with bone marrow stroma–tumour interactions bear therapeutic potential. The molecular characterisation of tumour–stroma interactions can identify new vulnerabilities, which could be therapeutically exploited. Full article

(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)

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14 pages, 1095 KiB

Open AccessReview

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

by Maissa Mhibik, Adrian Wiestner and Clare Sun

Int. J. Mol. Sci. 2020, 21(1), 68; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010068 - 20 Dec 2019

Cited by 35 | Viewed by 5075

Abstract

B-cell receptor (BCR) signaling and tumor–microenvironment crosstalk both drive chronic lymphocytic leukemia (CLL) pathogenesis. Within the microenvironment, tumor cells shape the T-cell compartment, which in turn supports tumor growth and survival. Targeting BCR signaling using Bruton tyrosine kinase inhibitors (BTKi) has become a highly successful treatment modality for CLL. Ibrutinib, the first-in-class BTKi, also inhibits Tec family kinases such as interleukin-2–inducible kinase (ITK), a proximal member of the T-cell receptor signaling cascade. It is increasingly recognized that ibrutinib modulates the T-cell compartment of patients with CLL. Understanding these T-cell changes is important for immunotherapy-based approaches aiming to increase the depth of response and to prevent or treat the emergence of resistant disease. Ibrutinib has been shown to improve T-cell function in CLL, resulting in the expansion of memory T cells, Th1 polarization, reduced expression of inhibitory receptors and improved immune synapse formation between T cells and CLL cells. Investigating the modulation of BTKi on the T-cell antitumoral function, and having a more complete understanding of changes in T cell behavior and function during treatment with BTKi therapy will inform the design of immunotherapy-based combination approaches and increase the efficacy of CLL therapy. Full article

(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)

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19 pages, 582 KiB

Open AccessReview

Immune and Inflammatory Cells of the Tumor Microenvironment Represent Novel Therapeutic Targets in Classical Hodgkin Lymphoma

by Eleonora Calabretta, Francesco d’Amore and Carmelo Carlo-Stella

Int. J. Mol. Sci. 2019, 20(21), 5503; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215503 - 05 Nov 2019

Cited by 25 | Viewed by 5434

Abstract

Classical Hodgkin Lymphoma (cHL) is a B-cell malignancy that, typically, responds well to standard therapies. However, patients who relapse after standard regimens or are refractory to induction therapy have a dismal outcome. The implementation of novel therapies such as the anti-CD30 monoclonal antibody Brentuximab Vedotin and immune checkpoint inhibitors has provided curative options for many of these patients. Nonetheless, responses are rarely durable, emphasizing the need for new agents. cHL is characterized by a unique microenvironment in which cellular and humoral components interact to promote tumor survival and dissemination. Knowledge of the complex composition of cHL microenvironment is constantly evolving; in particular, there is growing interest in certain cell subsets such as tumor-associated macrophages, myeloid-derived suppressor cells and neutrophils, all of which have a relevant role in the pathogenesis of the disease. The unique biology of the cHL microenvironment has provided opportunities to develop new drugs, many of which are currently being tested in preclinical and clinical settings. In this review, we will summarize novel insights in the crosstalk between tumor cells and non-malignant inflammatory cells. In addition, we will discuss the relevance of tumor-microenvironment interactions as potential therapeutic targets. Full article

(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)

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18 pages, 770 KiB

Open AccessReview

Engaging Cytotoxic T and NK Cells for Immunotherapy in Chronic Lymphocytic Leukemia

by Tom Hofland, Eric Eldering, Arnon P. Kater and Sanne H. Tonino

Int. J. Mol. Sci. 2019, 20(17), 4315; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20174315 - 03 Sep 2019

Cited by 22 | Viewed by 5380

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by an acquired immune dysfunction. CLL cells affect the phenotype and function of the entire spectrum of innate and adaptive immune cells, including monocytes, T cells, and natural killer (NK) cells, leading to a tumor-supportive environment and reduced immunosurveillance. Novel immunotherapies like immune checkpoint blockade, bi- and tri-specific antibodies, and chimeric antigen receptor (CAR) T cells use the patients’ immune system to induce therapeutic responses. Although these novel immunotherapies showed impressive results in several B cell lymphomas, responses in CLL were often disappointing. The strong immunomodulatory effect of CLL is believed to play a pivotal role in the low response rates to these immunotherapeutic strategies. In this review, we summarize how CLL influences the function of non-malignant lymphocytes, with a special focus on T and NK cells, two important cellular mediators for immunotherapy. Secondly, we provide a short overview of the activity of several immunotherapeutics in CLL, and discuss how novel strategies may overcome the disappointing response rates in CLL. Full article

(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)

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24 pages, 660 KiB

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Tumor Metabolism as a Regulator of Tumor–Host Interactions in the B-Cell Lymphoma Microenvironment—Fueling Progression and Novel Brakes for Therapy

by Anna C. Beielstein and Christian P. Pallasch

Int. J. Mol. Sci. 2019, 20(17), 4158; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20174158 - 26 Aug 2019

Cited by 13 | Viewed by 4396

Abstract

Tumor metabolism and its specific alterations have become an integral part of understanding functional alterations leading to malignant transformation and maintaining cancer progression. Here, we review the metabolic changes in B-cell neoplasia, focusing on the effects of tumor metabolism on the tumor microenvironment (TME). Particularly, innate and adaptive immune responses are regulated by metabolites in the TME such as lactate. With steadily increasing therapeutic options implicating or utilizing the TME, it has become essential to address the metabolic alterations in B-cell malignancy for therapeutic approaches. In this review, we discuss metabolic alterations of B-cell lymphoma, consequences for currently used therapy regimens, and novel approaches specifically targeting metabolism in the TME. Full article

(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)

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The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas

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