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Tumor Microenvironment: Interactions and Therapeutic Response
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Tumor Microenvironment: Interactions and Therapeutic Response

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

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 27239

Special Issue Editors

Dr. Nagaja Capitani

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Guest Editor
Università degli Studi di Siena, Siena, Italy
Prof. Dr. Cosima T. Baldari

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Guest Editor
Department of Life Science, Universita degli Studi di Siena, Siena, Italy
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Silvano Sozzani

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Guest Editor
Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy

Special Issue Information

Dear Colleagues,

Tumor cells constantly interact with their surrounding cells, which may include endothelial cells, fibroblasts, and innate as well as adaptive immune cells that, together with the extracellular matrix, form the tumor microenvironment. Cancer cells can functionally shape their microenvironment through the secretion of cytokines, chemokines, and other factors, resulting in the generation of a protective niche that fosters tumor survival and progression. Non-malignant cells present in the tumor microenvironment play a critical role at all the stages of carcinogenesis by promoting angiogenesis, invasion, metastasis, and chronic inflammation. Moreover, different components of the tumor microenvironment can significantly influence therapeutic responses and clinical outcomes by inducing drug resistance.

In this Special Issue “Tumor Microenvironment: Interactions and Therapeutic Response”, we will discuss the nature of the crosstalk between tumor cells and their microenvironment. We will explore the implications of these interactions for the improvement of therapeutics through simultaneous targeting of tumor cells and multiple components of the tumor microenvironment to efficiently exploit anticancer strategies and overcome drug resistance.

Dr. Nagaja Capitani
Prof. Dr. Cosima T. Baldari
Prof. Dr. Silvano Sozzani
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • endothelial cell
  • fibroblast
  • innate immunity
  • adaptive immunity
  • chemokine
  • cytokine
  • extracellular matrix
  • proliferation
  • drug resistance

Published Papers (7 papers)

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Research

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10 pages, 957 KiB  
Article
The Helicobacter pylori CagY Protein Drives Gastric Th1 and Th17 Inflammation and B Cell Proliferation in Gastric MALT Lymphoma
by Chiara Della Bella, Maria Felicia Soluri, Simone Puccio, Marisa Benagiano, Alessia Grassi, Jacopo Bitetti, Fabio Cianchi, Daniele Sblattero, Clelia Peano and Mario Milco D’Elios
Int. J. Mol. Sci. 2021, 22(17), 9459; https://doi.org/10.3390/ijms22179459 - 31 Aug 2021
Cited by 12 | Viewed by 2114
Abstract
Background: the neoplastic B cells of the Helicobacter pylori-related low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma proliferate in response to H. pylori, however, the nature of the H. pylori antigen responsible for proliferation is still unknown. The purpose of the study [...] Read more.
Background: the neoplastic B cells of the Helicobacter pylori-related low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma proliferate in response to H. pylori, however, the nature of the H. pylori antigen responsible for proliferation is still unknown. The purpose of the study was to dissect whether CagY might be the H. pylori antigen able to drive B cell proliferation. Methods: the B cells and the clonal progeny of T cells from the gastric mucosa of five patients with MALT lymphoma were compared with those of T cell clones obtained from five H. pylori–infected patients with chronic gastritis. The T cell clones were assessed for their specificity to H. pylori CagY, cytokine profile and helper function for B cell proliferation. Results: 22 of 158 CD4+ (13.9%) gastric clones from MALT lymphoma and three of 179 CD4+ (1.7%) clones from chronic gastritis recognized CagY. CagY predominantly drives Interferon-gamma (IFN-γ) and Interleukin-17 (IL-17) secretion by gastric CD4+ T cells from H. pylori-infected patients with low-grade gastric MALT lymphoma. All MALT lymphoma-derived clones dose dependently increased their B cell help, whereas clones from chronic gastritis lost helper activity at T-to-B-cell ratios greater than 1. Conclusion: the results obtained indicate that CagY drives both B cell proliferation and T cell activation in gastric MALT lymphomas. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interactions and Therapeutic Response)
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11 pages, 1977 KiB  
Communication
Hypoxia Enhances the Expression of RNASET2 in Human Monocyte-Derived Dendritic Cells: Role of PI3K/AKT Pathway
by Sara Monaci, Federica Coppola, Gaia Giuntini, Rossella Roncoroni, Francesco Acquati, Silvano Sozzani, Fabio Carraro and Antonella Naldini
Int. J. Mol. Sci. 2021, 22(14), 7564; https://doi.org/10.3390/ijms22147564 - 15 Jul 2021
Cited by 10 | Viewed by 2152
Abstract
Hypoxia is a key component of the tumor microenvironment (TME) and promotes not only tumor growth and metastasis, but also negatively affects infiltrating immune cells by impairing host immunity. Dendritic cells (DCs) are the most potent antigen-presenting cells and their biology is weakened [...] Read more.
Hypoxia is a key component of the tumor microenvironment (TME) and promotes not only tumor growth and metastasis, but also negatively affects infiltrating immune cells by impairing host immunity. Dendritic cells (DCs) are the most potent antigen-presenting cells and their biology is weakened in the TME in many ways, including the modulation of their viability. RNASET2 belongs to the T2 family of extracellular ribonucleases and, besides its nuclease activity, it exerts many additional functions. Indeed, RNASET2 is involved in several human pathologies, including cancer, and it is functionally relevant in the TME. RNASET2 functions are not restricted to cancer cells and its expression could be relevant also in other cell types which are important players in the TME, including DCs. Therefore, this study aimed to unravel the effect of hypoxia (2% O2) on the expression of RNASET2 in DCs. Here, we showed that hypoxia enhanced the expression and secretion of RNASET2 in human monocyte-derived DCs. This paralleled the HIF-1α accumulation and HIF-dependent and -independent signaling, which are associated with DCs’ survival/autophagy/apoptosis. RNASET2 expression, under hypoxia, was regulated by the PI3K/AKT pathway and was almost completely abolished by TLR4 ligand, LPS. Taken together, these results highlight how hypoxia- dependent and -independent pathways shape RNASET2 expression in DCs, with new perspectives on its implication for TME and, therefore, in anti-tumor immunity. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interactions and Therapeutic Response)
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20 pages, 665 KiB  
Review
Breast Cancer CAFs: Spectrum of Phenotypes and Promising Targeting Avenues
by Eiman Elwakeel and Andreas Weigert
Int. J. Mol. Sci. 2021, 22(21), 11636; https://doi.org/10.3390/ijms222111636 - 27 Oct 2021
Cited by 22 | Viewed by 3020
Abstract
Activation of the tumor-associated stroma to support tumor growth is a common feature observed in different cancer entities. This principle is exemplified by cancer-associated fibroblasts (CAFs), which are educated by the tumor to shape its development across all stages. CAFs can alter the [...] Read more.
Activation of the tumor-associated stroma to support tumor growth is a common feature observed in different cancer entities. This principle is exemplified by cancer-associated fibroblasts (CAFs), which are educated by the tumor to shape its development across all stages. CAFs can alter the extracellular matrix (ECM) and secrete a variety of different molecules. In that manner they have the capability to affect activation, survival, proliferation, and migration of other stromal cells and cancer cell themselves. Alteration of the ECM, desmoplasia, is a common feature of breast cancer, indicating a prominent role for CAFs in shaping tumor development in the mammary gland. In this review, we summarize the multiple roles CAFs play in mammary carcinoma. We discuss experimental and clinical strategies to interfere with CAFs function in breast cancer. Moreover, we highlight the issues arising from CAFs heterogeneity and the need for further research to identify CAFs subpopulation(s) that can be targeted to improve breast cancer therapy. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interactions and Therapeutic Response)
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20 pages, 1782 KiB  
Review
Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment
by Nagaja Capitani, Laura Patrussi and Cosima T. Baldari
Int. J. Mol. Sci. 2021, 22(20), 11221; https://doi.org/10.3390/ijms222011221 - 18 Oct 2021
Cited by 10 | Viewed by 3304
Abstract
Similar to Janus, the two-faced god of Roman mythology, the tumor microenvironment operates two opposing and often conflicting activities, on the one hand fighting against tumor cells, while on the other hand, favoring their proliferation, survival and migration to other sites to establish [...] Read more.
Similar to Janus, the two-faced god of Roman mythology, the tumor microenvironment operates two opposing and often conflicting activities, on the one hand fighting against tumor cells, while on the other hand, favoring their proliferation, survival and migration to other sites to establish metastases. In the tumor microenvironment, cytotoxic T cells—the specialized tumor-cell killers—also show this dual nature, operating their tumor-cell directed killing activities until they become exhausted and dysfunctional, a process promoted by cancer cells themselves. Here, we discuss the opposing activities of immune cells populating the tumor microenvironment in both cancer progression and anti-cancer responses, with a focus on cytotoxic T cells and on the molecular mechanisms responsible for the efficient suppression of their killing activities as a paradigm of the power of cancer cells to shape the microenvironment for their own survival and expansion. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interactions and Therapeutic Response)
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18 pages, 761 KiB  
Review
PD-1/PD-L1 in Cancer: Pathophysiological, Diagnostic and Therapeutic Aspects
by Enrico Munari, Francesca R. Mariotti, Linda Quatrini, Pietro Bertoglio, Nicola Tumino, Paola Vacca, Albino Eccher, Francesco Ciompi, Matteo Brunelli, Guido Martignoni, Giuseppe Bogina and Lorenzo Moretta
Int. J. Mol. Sci. 2021, 22(10), 5123; https://doi.org/10.3390/ijms22105123 - 12 May 2021
Cited by 59 | Viewed by 4134
Abstract
Immune evasion is a key strategy adopted by tumor cells to escape the immune system while promoting their survival and metastatic spreading. Indeed, several mechanisms have been developed by tumors to inhibit immune responses. PD-1 is a cell surface inhibitory receptor, which plays [...] Read more.
Immune evasion is a key strategy adopted by tumor cells to escape the immune system while promoting their survival and metastatic spreading. Indeed, several mechanisms have been developed by tumors to inhibit immune responses. PD-1 is a cell surface inhibitory receptor, which plays a major physiological role in the maintenance of peripheral tolerance. In pathological conditions, activation of the PD-1/PD-Ls signaling pathway may block immune cell activation, a mechanism exploited by tumor cells to evade the antitumor immune control. Targeting the PD-1/PD-L1 axis has represented a major breakthrough in cancer treatment. Indeed, the success of PD-1 blockade immunotherapies represents an unprecedented success in the treatment of different cancer types. To improve the therapeutic efficacy, a deeper understanding of the mechanisms regulating PD-1 expression and signaling in the tumor context is required. We provide an overview of the current knowledge of PD-1 expression on both tumor-infiltrating T and NK cells, summarizing the recent evidence on the stimuli regulating its expression. We also highlight perspectives and limitations of the role of PD-L1 expression as a predictive marker, discuss well-established and novel potential approaches to improve patient selection and clinical outcome and summarize current indications for anti-PD1/PD-L1 immunotherapy. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interactions and Therapeutic Response)
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24 pages, 1203 KiB  
Review
The Bone Marrow Niche in B-Cell Acute Lymphoblastic Leukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia
by Erica Dander, Chiara Palmi, Giovanna D’Amico and Giovanni Cazzaniga
Int. J. Mol. Sci. 2021, 22(9), 4426; https://doi.org/10.3390/ijms22094426 - 23 Apr 2021
Cited by 26 | Viewed by 5007
Abstract
Genetic lesions predisposing to pediatric B-cell acute lymphoblastic leukemia (B-ALL) arise in utero, generating a clinically silent pre-leukemic phase. We here reviewed the role of the surrounding bone marrow (BM) microenvironment in the persistence and transformation of pre-leukemic clones into fully leukemic cells. [...] Read more.
Genetic lesions predisposing to pediatric B-cell acute lymphoblastic leukemia (B-ALL) arise in utero, generating a clinically silent pre-leukemic phase. We here reviewed the role of the surrounding bone marrow (BM) microenvironment in the persistence and transformation of pre-leukemic clones into fully leukemic cells. In this context, inflammation has been highlighted as a crucial microenvironmental stimulus able to promote genetic instability, leading to the disease manifestation. Moreover, we focused on the cross-talk between the bulk of leukemic cells with the surrounding microenvironment, which creates a “corrupted” BM malignant niche, unfavorable for healthy hematopoietic precursors. In detail, several cell subsets, including stromal, endothelial cells, osteoblasts and immune cells, composing the peculiar leukemic niche, can actively interact with B-ALL blasts. Through deregulated molecular pathways they are able to influence leukemia development, survival, chemoresistance, migratory and invasive properties. The concept that the pre-leukemic and leukemic cell survival and evolution are strictly dependent both on genetic lesions and on the external signals coming from the microenvironment paves the way to a new idea of dual targeting therapeutic strategy. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interactions and Therapeutic Response)
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14 pages, 1316 KiB  
Review
Granulocytes and Cells of Granulocyte Origin—The Relevant Players in Colorectal Cancer
by Izabela Siemińska, Ewa Poljańska and Jarek Baran
Int. J. Mol. Sci. 2021, 22(7), 3801; https://doi.org/10.3390/ijms22073801 - 06 Apr 2021
Cited by 5 | Viewed by 6402
Abstract
Colorectal cancer (CRC) is one of the most common malignancy and cause of cancer death worldwide, and it still remains a therapeutic challenge for western medicine. There is strong evidence that, in addition to genetic predispositions, environmental factors have also a substantial impact [...] Read more.
Colorectal cancer (CRC) is one of the most common malignancy and cause of cancer death worldwide, and it still remains a therapeutic challenge for western medicine. There is strong evidence that, in addition to genetic predispositions, environmental factors have also a substantial impact in CRC development. The risk of CRC is attributed, among others to dietary habits, alcohol consumption, whereas physical activity, food containing dietary fiber, dairy products, and calcium supplements have a protective effect. Despite progress in the available therapies, surgery remains a basic treatment option for CRC. Implementation of additional methods of treatment such as chemo- and/or targeted immunotherapy, improved survival rates, however, the results are still far from satisfactory. One of the reasons may be the lack of deeper understanding of the interactions between the tumor and different types of cells, including tumor infiltrating granulocytes. While the role of neutrophils is quite well explored in many cancers, role of eosinophils and basophils is often underestimated. As part of this review, we focused on the function of different granulocyte subsets in CRC, emphasizing the beneficial role of eosinophils and basophils, as well as dichotomic mode of neutrophils action. In addition, we addressed the current knowledge on cells of granulocyte origin, specifically granulocytic myeloid derived suppressor cells (Gr-MDSCs) and their role in development and progression of CRC. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interactions and Therapeutic Response)
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