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Immune Microenvironment in Solid and Hematological Malignancies
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Immune Microenvironment in Solid and Hematological Malignancies

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Hematology".

Deadline for manuscript submissions: closed (25 May 2023) | Viewed by 17607

Special Issue Editor

Dr. Antonio G. Solimando

E-Mail Website
Guest Editor
Unit of Internal Medicine “Guido Baccelli”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
Interests: multiple myeloma; microenvironment; oncology; angiogenesis; hematology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is my pleasure to invite you to contribute to the upcoming Special Issue of the Journal of Clinical Medicine devoted entitled “Immune Microenvironment in Solid and Hematological Malignancies”. The aim of this issue is to provide an overview of current knowledge on the crucial mechanisms promoting tumor niche interactions and mediating immunosuppression during cancer development and progression.

Despite significant improvements in therapy during the last decade, most cancer patients develop refractory disease over time. Treatment of refractory malignancy is a major challenge, likely due to the still poorly characterized inter- and intratumor heterogeneity and the complex interplay of neoplastic cells with the tumor microenvironment. In particular, there is an urgent need to unravel how these features of the cancer neighborhood are linked to molecular mechanisms of drug resistance and aggressive phenotype. The aim of this issue is to review current knowledge on the crucial mechanisms promoting malignant evolution and mediating immunosuppression during cancer development and progression. As is now well known, tumors grow and evolve through a constant crosstalk with the surrounding milieu, and emerging evidence indicates that several gatekeepers and immune-tolerogenic environments frequently occur simultaneously in response to this crosstalk. Accordingly, strategies combining anti-tumor therapy and immunotherapy seem to hold the promise to tip the balance of the cancer niche and improve patient outcomes.

All manuscripts will be peer-reviewed according to standard journal procedures and policies.

I hope that you will be able to accept this invitation and contribute to the success of this Special Issue. I look forward to collaborating with you.

Sincerely,

Dr. Antonio G. Solimando
Guest Editor

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. Journal of Clinical Medicine 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 2600 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

  • immune cells
  • immune checkpoints
  • immunotherapy
  • microenvironment
  • tumor angiogenesis

Published Papers (7 papers)

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Editorial

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3 pages, 203 KiB  
Editorial
The Urgent Need for Precision Medicine in Cancer and Its Microenvironment: The Paradigmatic Case of Multiple Myeloma
by Antonio Giovanni Solimando, Markus Krebs, Max Bittrich and Hermann Einsele
J. Clin. Med. 2022, 11(18), 5461; https://doi.org/10.3390/jcm11185461 - 16 Sep 2022
Cited by 2 | Viewed by 1358
Abstract
Precision medicine is particularly relevant for cancer and microenvironment deconvolution for therapeutic purposes in hematological and non-hematological malignancies [...] Full article
(This article belongs to the Special Issue Immune Microenvironment in Solid and Hematological Malignancies)

Review

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10 pages, 1687 KiB  
Review
The Complexity of the Tumor Microenvironment in Hepatocellular Carcinoma and Emerging Therapeutic Developments
by Antonella Argentiero, Antonella Delvecchio, Rossella Fasano, Alessandro Andriano, Ingrid Catalina Caradonna, Riccardo Memeo and Vanessa Desantis
J. Clin. Med. 2023, 12(23), 7469; https://doi.org/10.3390/jcm12237469 - 02 Dec 2023
Cited by 2 | Viewed by 1773
Abstract
This review explores various aspects of the HCC TME, including both cellular and non-cellular components, to elucidate their roles in tumor development and progression. Specifically, it highlights the significance of cancer-associated fibroblasts (CAFs) and their contributions to tumor progression, angiogenesis, immune suppression, and [...] Read more.
This review explores various aspects of the HCC TME, including both cellular and non-cellular components, to elucidate their roles in tumor development and progression. Specifically, it highlights the significance of cancer-associated fibroblasts (CAFs) and their contributions to tumor progression, angiogenesis, immune suppression, and therapeutic resistance. Moreover, this review emphasizes the role of immune cells, such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T-cells (Tregs), in shaping the immunosuppressive microenvironment that promotes tumor growth and immune evasion. Furthermore, we also focused only on the non-cellular components of the HCC TME, including the extracellular matrix (ECM) and the role of hypoxia-induced angiogenesis. Alterations in the composition of ECM and stiffness have been implicated in tumor invasion and metastasis, while hypoxia-driven angiogenesis promotes tumor growth and metastatic spread. The molecular mechanisms underlying these processes, including the activation of hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF) signaling, are also discussed. In addition to elucidating the complex TME of HCC, this review focuses on emerging therapeutic strategies that target the TME. It highlights the potential of second-line treatments, such as regorafenib, cabozantinib, and ramucirumab, in improving overall survival for advanced HCC patients who have progressed on or were intolerant to first-line therapy. Furthermore, this review explores the implications of the Barcelona Clinic Liver Cancer (BCLC) staging and classification system in guiding HCC management decisions. The BCLC system, which incorporates tumor stage, liver function, and performance status, provides a framework for treatment stratification and prognosis prediction in HCC patients. The insights gained from this review contribute to the development of novel therapeutic interventions and personalized treatment approaches for HCC patients, ultimately improving clinical outcomes in this challenging disease. Full article
(This article belongs to the Special Issue Immune Microenvironment in Solid and Hematological Malignancies)
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16 pages, 868 KiB  
Review
Cellular and Molecular Players in the Tumor Microenvironment of Renal Cell Carcinoma
by Francesco Lasorsa, Monica Rutigliano, Martina Milella, Matteo Ferro, Savio Domenico Pandolfo, Felice Crocetto, Octavian Sabin Tataru, Riccardo Autorino, Michele Battaglia, Pasquale Ditonno and Giuseppe Lucarelli
J. Clin. Med. 2023, 12(12), 3888; https://doi.org/10.3390/jcm12123888 - 07 Jun 2023
Cited by 32 | Viewed by 2518
Abstract
Globally, clear-cell renal cell carcinoma (ccRCC) represents the most prevalent type of kidney cancer. Surgery plays a key role in the treatment of this cancer, although one third of patients are diagnosed with metastatic ccRCC and about 25% of patients will develop a [...] Read more.
Globally, clear-cell renal cell carcinoma (ccRCC) represents the most prevalent type of kidney cancer. Surgery plays a key role in the treatment of this cancer, although one third of patients are diagnosed with metastatic ccRCC and about 25% of patients will develop a recurrence after nephrectomy with curative intent. Molecular-target-based agents, such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), are recommended for advanced cancers. In addition to cancer cells, the tumor microenvironment (TME) includes non-malignant cell types embedded in an altered extracellular matrix (ECM). The evidence confirms that interactions among cancer cells and TME elements exist and are thought to play crucial roles in the development of cancer, making them promising therapeutic targets. In the TME, an unfavorable pH, waste product accumulation, and competition for nutrients between cancer and immune cells may be regarded as further possible mechanisms of immune escape. To enhance immunotherapies and reduce resistance, it is crucial first to understand how the immune cells work and interact with cancer and other cancer-associated cells in such a complex tumor microenvironment. Full article
(This article belongs to the Special Issue Immune Microenvironment in Solid and Hematological Malignancies)
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30 pages, 811 KiB  
Review
Extracellular Vesicles and Their Roles in the Tumor Immune Microenvironment
by Antonia Reale, Tiffany Khong and Andrew Spencer
J. Clin. Med. 2022, 11(23), 6892; https://doi.org/10.3390/jcm11236892 - 22 Nov 2022
Cited by 9 | Viewed by 2378
Abstract
Tumor cells actively incorporate molecules (e.g., proteins, lipids, RNA) into particles named extracellular vesicles (EVs). Several groups have demonstrated that EVs can be transferred to target (recipient) cells, making EVs an important means of intercellular communication. Indeed, EVs are able to modulate the [...] Read more.
Tumor cells actively incorporate molecules (e.g., proteins, lipids, RNA) into particles named extracellular vesicles (EVs). Several groups have demonstrated that EVs can be transferred to target (recipient) cells, making EVs an important means of intercellular communication. Indeed, EVs are able to modulate the functions of target cells by reprogramming signaling pathways. In a cancer context, EVs promote the formation of a supportive tumor microenvironment (TME) and (pre)metastatic niches. Recent studies have revealed that immune cells, tumor cells and their secretome, including EVs, promote changes in the TME and immunosuppressive functions of immune cells (e.g., natural killer, dendritic cells, T and B cells, monocytes, macrophages) that allow tumor cells to establish and propagate. Despite the growing knowledge on EVs and on their roles in cancer and as modulators of the immune response/escape, the translation into clinical practice remains in its early stages, hence requiring improved translational research in the EVs field. Here, we comprehensively review the current knowledge and most recent research on the roles of EVs in tumor immune evasion and immunosuppression in both solid tumors and hematological malignancies. We also highlight the clinical utility of EV-mediated immunosuppression targeting and EV-engineering. Importantly, we discuss the controversial role of EVs in cancer biology, current limitations and future perspectives to further the EV knowledge into clinical practice. Full article
(This article belongs to the Special Issue Immune Microenvironment in Solid and Hematological Malignancies)
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20 pages, 957 KiB  
Review
Pathways of Angiogenic and Inflammatory Cytokines in Multiple Myeloma: Role in Plasma Cell Clonal Expansion and Drug Resistance
by Assunta Melaccio, Antonia Reale, Ilaria Saltarella, Vanessa Desantis, Aurelia Lamanuzzi, Sebastiano Cicco, Maria Antonia Frassanito, Angelo Vacca and Roberto Ria
J. Clin. Med. 2022, 11(21), 6491; https://doi.org/10.3390/jcm11216491 - 01 Nov 2022
Cited by 6 | Viewed by 2241
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy, and despite the introduction of innovative therapies, remains an incurable disease. Identifying early and minimally or non-invasive biomarkers for predicting clinical outcomes and therapeutic responses is an active field of investigation. Malignant plasma [...] Read more.
Multiple myeloma (MM) is the second most common hematological malignancy, and despite the introduction of innovative therapies, remains an incurable disease. Identifying early and minimally or non-invasive biomarkers for predicting clinical outcomes and therapeutic responses is an active field of investigation. Malignant plasma cells (PCs) reside in the bone marrow (BM) microenvironment (BMME) which comprises cells (e.g., tumour, immune, stromal cells), components of the extracellular matrix (ECM) and vesicular and non-vesicular (soluble) molecules, all factors that support PCs’ survival and proliferation. The interaction between PCs and BM stromal cells (BMSCs), a hallmark of MM progression, is based not only on intercellular interactions but also on autocrine and paracrine circuits mediated by soluble or vesicular components. In fact, PCs and BMSCs secrete various cytokines, including angiogenic cytokines, essential for the formation of specialized niches called “osteoblastic and vascular niches”, thus supporting neovascularization and bone disease, vital processes that modulate the pathophysiological PCs–BMME interactions, and ultimately promoting disease progression. Here, we aim to discuss the roles of cytokines and growth factors in pathogenetic pathways in MM and as prognostic and predictive biomarkers. We also discuss the potential of targeted drugs that simultaneously block PCs’ proliferation and survival, PCs–BMSCs interactions and BMSCs activity, which may represent the future goal of MM therapy. Full article
(This article belongs to the Special Issue Immune Microenvironment in Solid and Hematological Malignancies)
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20 pages, 1966 KiB  
Review
The Leading Role of the Immune Microenvironment in Multiple Myeloma: A New Target with a Great Prognostic and Clinical Value
by Vanessa Desantis, Francesco Domenico Savino, Antonietta Scaringella, Maria Assunta Potenza, Carmela Nacci, Maria Antonia Frassanito, Angelo Vacca and Monica Montagnani
J. Clin. Med. 2022, 11(9), 2513; https://doi.org/10.3390/jcm11092513 - 29 Apr 2022
Cited by 16 | Viewed by 4170
Abstract
Multiple myeloma (MM) is a plasma cell (PC) malignancy whose development flourishes in the bone marrow microenvironment (BMME). The BMME components’ immunoediting may foster MM progression by favoring initial immunotolerance and subsequent tumor cell escape from immune surveillance. In this dynamic process, immune [...] Read more.
Multiple myeloma (MM) is a plasma cell (PC) malignancy whose development flourishes in the bone marrow microenvironment (BMME). The BMME components’ immunoediting may foster MM progression by favoring initial immunotolerance and subsequent tumor cell escape from immune surveillance. In this dynamic process, immune effector cells are silenced and become progressively anergic, thus contributing to explaining the mechanisms of drug resistance in unresponsive and relapsed MM patients. Besides traditional treatments, several new strategies seek to re-establish the immunological balance in the BMME, especially in already-treated MM patients, by targeting key components of the immunoediting process. Immune checkpoints, such as CXCR4, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), PD-1, and CTLA-4, have been identified as common immunotolerance steps for immunotherapy. B-cell maturation antigen (BCMA), expressed on MMPCs, is a target for CAR-T cell therapy, antibody-(Ab) drug conjugates (ADCs), and bispecific mAbs. Approved anti-CD38 (daratumumab, isatuximab), anti-VLA4 (natalizumab), and anti-SLAMF7 (elotuzumab) mAbs interfere with immunoediting pathways. New experimental drugs currently being evaluated (CD137 blockers, MSC-derived microvesicle blockers, CSF-1/CSF-1R system blockers, and Th17/IL-17/IL-17R blockers) or already approved (denosumab and bisphosphonates) may help slow down immune escape and disease progression. Thus, the identification of deregulated mechanisms may identify novel immunotherapeutic approaches to improve MM patients’ outcomes. Full article
(This article belongs to the Special Issue Immune Microenvironment in Solid and Hematological Malignancies)
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Other

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11 pages, 2070 KiB  
Brief Report
A Proliferation-Inducing Ligand and B-Cell Activating Factor Are Upregulated in Patients with Essential Thrombocythemia
by Lukasz Bolkun, Marlena Tynecka, Tomasz Wasiluk, Jaroslaw Piszcz, Aleksandra Starosz, Kamil Grubczak, Marcin Moniuszko and Andrzej Eljaszewicz
J. Clin. Med. 2022, 11(16), 4663; https://doi.org/10.3390/jcm11164663 - 09 Aug 2022
Cited by 1 | Viewed by 1447
Abstract
A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are cytokines belonging to the tumor necrosis factor family which play an essential role in B-cell maturation, differentiation, and survival. Recent evidence indicates their importance in hematological disorders; however, their function in essential thrombocytosis [...] Read more.
A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are cytokines belonging to the tumor necrosis factor family which play an essential role in B-cell maturation, differentiation, and survival. Recent evidence indicates their importance in hematological disorders; however, their function in essential thrombocytosis (ET) pathogenesis remains elusive. Therefore, we aimed to analyze the role of APRIL and BAFF in megakaryocytopoiesis in ET patients. We observed elevated levels of APRIL and BAFF in the plasma of ET patients compared with healthy controls, while no differences were found among patients with different JAK2(V617F) statuses. In addition, APRIL levels were positively associated with the number of platelets and WBC count. In the bone marrow, APRIL but not BAFF levels were higher in ET patients with the JAK2(V617F) mutation; however, JAK2(V617F)-negative patients showed slightly reduced levels of BAFF. In ET patients, we showed that the differentiation of CD34+ progenitor cells towards megakaryocytes induces the expression of both APRIL and BAFF. More importantly, APRIL neutralization significantly reduced platelet production. In conclusion, our data provide evidence that blocking APRIL signaling, which acts as an autocrine growth factor for terminal megakaryocytopoiesis, inhibits platelet production in ET patients, regardless of the status of JAK2(V617F) mutation. Full article
(This article belongs to the Special Issue Immune Microenvironment in Solid and Hematological Malignancies)
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