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Tumor Immune Microenvironment in Lymphoproliferative Syndromes

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 16569

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Special Issue Editors

Dr. Margarita Sánchez-Beato

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Guest Editor

Lymphoma Research Group, Clinical Oncology Department, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana (IDIPHISA). c/ Joaquín Rodrigo 2. Majadahonda, 28222 Madrid, Spain
Interests: molecular pathology; molecular genetics; biotechnology; lymphoma biology

Dr. Luis De la Cruz-Merino

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Guest Editor

Clinical Oncology Department, Virgen Macarena University Hospital. Medicine Department, Universidad de Sevilla. Avda Dr Fedriani s/n, 41009 Seville, Spain
Interests: immunology; immunotherapy; lymphoma; melanoma; breast cancer; immune biomarkers discovery

Special Issue Information

Dear Colleagues,

Lymphoproliferative syndromes constitute an extensive and heterogeneous group of oncological diseases with different features, biological behavior, and clinical evolution. The precise molecular characterization of lymphomas is gaining in interest and relevance, as it may represent the first step in the design a successful therapeutic strategy to keep disease under control. However, the complexity of lymphomas goes beyond the molecular abnormalities of malignant lymphocytes. The specific surrounding tumor microenvironment (TME) has been revealed as a factor of paramount relevance, that in some cases harbors prognostic and predictive information which can be crucial from a clinical perspective, as the availability of different types of immunotherapies has dramatically increased in the last few years.

In this Special Issue, reputed basic and clinical experts in the lymphoma field will try to thoroughly describe the specific immune TME in these diseases, from different angles, in order to identify potential new therapeutic targets that could ameliorate clinical outcomes in patients with lymphoproliferative syndromes.

Dr. Margarita Sánchez-Beato
Dr. Luis De la Cruz-Merino
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

tumor microenvironment
immune cells
therapeutic targets
immunotherapy
lymphomas

Published Papers (6 papers)

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Research

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18 pages, 2561 KiB

Open AccessArticle

Expression of PD-1, PD-L1 and PD-L2 in Lymphomas in Patients with Pre-Existing Rheumatic Diseases—A Possible Association with High Rheumatoid Arthritis Disease Activity

by Erik Hellbacher, Christer Sundström, Daniel Molin, Eva Baecklund and Peter Hollander

Cancers 2022, 14(6), 1509; https://doi.org/10.3390/cancers14061509 - 15 Mar 2022

Cited by 4 | Viewed by 2112

Abstract

Current research seeks to identify subgroups of non-Hodgkin lymphoma (NHL) patients responsive to PD-1 blocking agents. Whether patients with pre-existing rheumatic diseases might constitute such a subgroup is unknown. We determined intratumoral expression of PD-1 and its ligands in lymphoma patients with pre-existing rheumatic diseases. We included 215 patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or Sjögren’s syndrome with subsequent lymphoma and 74 diffuse large B-cell lymphoma (DLBCL) controls without rheumatic disease. PD-1 and PD-ligand immunohistochemical markers were applied on tumor tissue microarrays. The number of PD-1+ tumor infiltrating leukocytes (TILs) and proportions of PD-L1+ and PD-L2+ tumor cells and TILs were calculated and correlated with clinical data. Expression of PD-L1 in tumor cells and TILs was highest in classical Hodgkin lymphoma and DLBCL. In DLBCLs, expression of PD-1 in TILs and PD-L1 in tumor cells was similar in RA, SLE and controls. In RA-DLBCL, high expression of PD-L1 in tumor cells was significantly more common in patients with the most severe RA disease and was associated with inferior overall survival in multivariable analysis. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment in Lymphoproliferative Syndromes)

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14 pages, 15417 KiB

Open AccessArticle

Lower Survival and Increased Circulating Suppressor Cells in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma with Deficit of Vitamin D Levels Using R-GDP Plus Lenalidomide (R2-GDP): Results from the R2-GDP-GOTEL Trial

by Carlos Jiménez-Cortegana, Pilar M. Sánchez-Martínez, Natalia Palazón-Carrión, Esteban Nogales-Fernández, Fernando Henao-Carrasco, Alejandro Martín García-Sancho, Antonio Rueda, Mariano Provencio, Luis de la Cruz-Merino and Víctor Sánchez-Margalet

Cancers 2021, 13(18), 4622; https://doi.org/10.3390/cancers13184622 - 15 Sep 2021

Cited by 6 | Viewed by 2237

Abstract

The search of prognostic factors is a priority in diffuse large B-cell lymphoma (DLBCL) due to its aggressiveness. We have recently found that the level of circulating MDSCs is a good marker of survival in a translational study based on a trial (EudraCT Number: 2014-001620-29), using lenalidomide combined with R-GDP (rituximab plus gemcitabine, cisplatin, and dexamethasone). Since Vitamin D is a known immunomodulator, we have studied blood levels of these cell populations comparing patients with deficit of vitamin D levels (<15 ng/mL with those with normal levels >15 ng/mL. Mann–Whitney U test was used to compare cells distributions between groups, Wilcoxon test to compare cells distribution at different times and Spearman test to measure the association between cell populations. Patients with vitamin D deficit maintained the increased level of immune suppressor cells, whereas we observed a depletion of all immune suppressor cells in patients with normal vitamin D levels. In conclusion, we have confirmed the importance of vitamin D in the response to treatment in R/R DLBCL, suggesting that vitamin D deficit may be involved in the immune deficit of these patients, and thus, vitamin D supplementation in these patients may help to obtain a better response, warranting further investigation. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment in Lymphoproliferative Syndromes)

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Review

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14 pages, 2105 KiB

Open AccessReview

Combined High-Throughput Approaches Reveal the Signals Driven by Skin and Blood Environments and Define the Tumor Heterogeneity in Sézary Syndrome

by Cristina Cristofoletti, Antonella Bresin, Martina Fioretti, Giandomenico Russo and Maria Grazia Narducci

Cancers 2022, 14(12), 2847; https://doi.org/10.3390/cancers14122847 - 9 Jun 2022

Cited by 1 | Viewed by 2151

Abstract

Sézary syndrome (SS) is an aggressive variant of cutaneous t-cell lymphoma characterized by the accumulation of neoplastic CD4+ lymphocytes—the SS cells—mainly in blood, lymph nodes, and skin. The tumor spread pattern of SS makes this lymphoma a unique model of disease that allows a concurrent blood and skin sampling for analysis. This review summarizes the recent studies highlighting the transcriptional programs triggered by the crosstalk between SS cells and blood–skin microenvironments. Emerging data proved that skin-derived SS cells show consistently higher activation/proliferation rates, mainly driven by T-cell receptor signaling with respect to matched blood SS cells that instead appear quiescent. Biochemical analyses also demonstrated an hyperactivation of PI3K/AKT/mTOR, a targetable pathway by multiple inhibitors currently in clinical trials, in skin SS cells compared with a paired blood counterpart. These results indicated that active and quiescent SS cells coexist in this lymphoma, and that they could be respectively treated with different therapeutics. Finally, this review underlines the more recent discoveries into the heterogeneity of circulating SS cells, highlighting a series of novel markers that could improve the diagnosis and that represent novel therapeutic targets (GPR15, PTPN13, KLRB1, and ITGB1) as well as new genetic markers (PD-1 and CD39) able to stratify SS patients for disease aggressiveness. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment in Lymphoproliferative Syndromes)

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16 pages, 892 KiB

Open AccessReview

Unveiling the Role of the Tumor Microenvironment in the Treatment of Follicular Lymphoma

by Mariola Blanco, Ana Collazo-Lorduy, Natalia Yanguas-Casás, Virginia Calvo and Mariano Provencio

Cancers 2022, 14(9), 2158; https://doi.org/10.3390/cancers14092158 - 26 Apr 2022

Cited by 3 | Viewed by 3000

Abstract

Follicular lymphomas (FL) are neoplasms that resemble normal germinal center (GC) B-cells. Normal GC and neoplastic follicles contain non-neoplastic cells such as T-cells, follicular dendritic cells, cancer associated fibroblasts, and macrophages, which define the tumor microenvironment (TME), which itself is an essential factor in tumor cell survival. The main characteristics of the TME in FL are an increased number of follicular regulatory T-cells (T_reg) and follicular helper T-cells (T_fh), M2-polarization of macrophages, and the development of a nodular network by stromal cells that creates a suitable niche for tumor growth. All of them play important roles in tumor angiogenesis, inhibition of apoptosis, and immune evasion, which are key factors in tumor progression and transformation risk. Based on these findings, novel therapies have been developed to target specific mutations present in the TME cells, restore immune suppression, and modulate TME. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment in Lymphoproliferative Syndromes)

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30 pages, 1315 KiB

Open AccessReview

Tumor Immune Microenvironment in Lymphoma: Focus on Epigenetics

by Daniel J. García-Domínguez, Lourdes Hontecillas-Prieto, Natalia Palazón-Carrión, Carlos Jiménez-Cortegana, Víctor Sánchez-Margalet and Luis de la Cruz-Merino

Cancers 2022, 14(6), 1469; https://doi.org/10.3390/cancers14061469 - 13 Mar 2022

Cited by 10 | Viewed by 3211

Abstract

Lymphoma is a neoplasm arising from B or T lymphocytes or natural killer cells characterized by clonal lymphoproliferation. This tumor comprises a diverse and heterogeneous group of malignancies with distinct clinical, histopathological, and molecular characteristics. Despite advances in lymphoma treatment, clinical outcomes of patients with relapsed or refractory disease remain poor. Thus, a deeper understanding of molecular pathogenesis and tumor progression of lymphoma is required. Epigenetic alterations contribute to cancer initiation, progression, and drug resistance. In fact, over the past decade, dysregulation of epigenetic mechanisms has been identified in lymphomas, and the knowledge of the epigenetic aberrations has led to the emergence of the promising epigenetic therapy field in lymphoma tumors. However, epigenetic aberrations in lymphoma not only have been found in tumor cells, but also in cells from the tumor microenvironment, such as immune cells. Whereas the epigenetic dysregulation in lymphoma cells is being intensively investigated, there are limited studies regarding the epigenetic mechanisms that affect the functions of immune cells from the tumor microenvironment in lymphoma. Therefore, this review tries to provide a general overview of epigenetic alterations that affect both lymphoma cells and infiltrating immune cells within the tumor, as well as the epigenetic cross-talk between them. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment in Lymphoproliferative Syndromes)

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17 pages, 1091 KiB

Open AccessReview

PI3Kδ Inhibitors as Immunomodulatory Agents for the Treatment of Lymphoma Patients

by Chiara Tarantelli, Lisa Argnani, Pier Luigi Zinzani and Francesco Bertoni

Cancers 2021, 13(21), 5535; https://doi.org/10.3390/cancers13215535 - 4 Nov 2021

Cited by 17 | Viewed by 3055

Abstract

The development of small molecules able to block specific or multiple isoforms of phosphoinositide 3-kinases (PI3K) has already been an active field of research for many years in the cancer field. PI3Kδ inhibitors are among the targeted agents most extensively studied for the treatment of lymphoma patients and PI3Kδ inhibitors are already approved by regulatory agencies. More recently, it became clear that the anti-tumor activity of PI3K inhibitors might not be due only to a direct effect on the cancer cells but it can also be mediated via inhibition of the kinases in non-neoplastic cells present in the tumor microenvironment. T-cells represent an important component of the tumor microenvironment and they comprise different subpopulations that can have both anti- and pro-tumor effects. In this review article, we discuss the effects that PI3Kδ inhibitors exert on the immune system with a particular focus on the T-cell compartment. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment in Lymphoproliferative Syndromes)

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