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The Role of Tumor Microenvironment in Solid Tumors: Development of...
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The Role of Tumor Microenvironment in Solid Tumors: Development of Cancer Research

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

Deadline for manuscript submissions: 31 March 2025 | Viewed by 4722

Special Issue Editors

Prof. Dr. Antonio Giuseppe Naccarato

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Guest Editor
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
Interests: breast Cancer; neuropathology; molecular pathology
Special Issues, Collections and Topics in MDPI journals
Dr. Giuseppe Fanelli

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Guest Editor
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
Interests: breast cancer; urogenital cancers; neuropathology; molecular pathology; digital pathology; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals
Dr. Andres Martin Acosta

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Guest Editor
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Interests: urology; genitourinary pathology; prostate cancer; molecular pathology; soft tissue tumors; translational research
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Groundbreaking research and cutting-edge technologies have shed light on tumors’ complex and heterogeneous composition, highlighting the pivotal role of the tumor microenvironment (TME) in cancer initiation, progression, metastasization, and immune escape. The investigation of the multifaceted bidirectional interactions between these two aspects has led to significant developments in cancer research. However, several aspects still remain unclear, necessitating innovative studies with unique approaches which could revolutionize the understanding of cancer mechanisms, and lay the foundations for novel therapeutic strategies targeted against TME components.

This Special Issue in Cancers titled ‘The Role of Tumor Microenvironment in Solid Tumors: New Developments in Cancer Research’ will try to draw a complete portrait of the current state of knowledge on TME, highlighting the pioneering findings that could have a promising translational application. We welcome original research articles, reviews (either systematic or discursive), and short communications with significant preliminary results.

Prof. Dr. Antonio Giuseppe Naccarato
Dr. Giuseppe Fanelli
Dr. Andres Martin Acosta
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 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 microenvironment
  • solid tumors
  • prognostic biomarkers
  • predictive biomarkers
  • translational research

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Published Papers (4 papers)

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Research

17 pages, 6848 KiB  
Article
Deciphering CD59: Unveiling Its Role in Immune Microenvironment and Prognostic Significance
by Bhaumik Patel, Ashok Silwal, Mohamed Ashraf Eltokhy, Shreyas Gaikwad, Marina Curcic, Jalpa Patel and Sahdeo Prasad
Cancers 2024, 16(21), 3699; https://doi.org/10.3390/cancers16213699 - 1 Nov 2024
Viewed by 793
Abstract
Background: CD59, a GPI-anchored membrane protein, protects cancer cells from complement-dependent cytotoxicity (CDC) by inhibiting the formation of the membrane attack complex (MAC). It has been demonstrated to be overexpressed in most solid tumors, where it facilitates tumor cell escape from complement surveillance. [...] Read more.
Background: CD59, a GPI-anchored membrane protein, protects cancer cells from complement-dependent cytotoxicity (CDC) by inhibiting the formation of the membrane attack complex (MAC). It has been demonstrated to be overexpressed in most solid tumors, where it facilitates tumor cell escape from complement surveillance. The role of CD59 in cancer growth and interactions between CD59 and immune cells that modulate immune evasion has not been well explored. Methods: Using cancer patient database from The Cancer Genome Atlas (TCGA) and other public databases, we analyzed CD59 expression, its prognostic significance, and its association with immune cell infiltration in the tumor microenvironment, identifying associated genomic and functional networks and validating findings with invitro cell-line experimental data. Results: This article describes the abundant expression of CD59 in multiple tumors such as cervical squamous cell carcinoma (CESC), kidney renal cell carcinoma (KIRC), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), and stomach adenocarcinoma (STAD), as well as in pan-cancer, using The Cancer Genome Atlas (TCGA) database and confirmed using multiple cancer cell lines. The expression of CD59 significantly alters the overall survival (OS) of patients with multiple malignancies such as CESC, GBM, HNSC, and STAD. Further, the correlation between CD59 and Treg and/or MDSC in the tumor microenvironment (TME) has shown to be strongly associated with poor outcomes in CESC, GBM, HNSC, and STAD as these tumors express high FOXP3 compared to KIRC. Moreover, unfavorable outcomes were strongly associated with the expression of CD59 and M2 tumor-associated macrophage infiltration in the TME via the IL10/pSTAT3 pathway in CESC and GBM but not in KIRC. In addition, TGFβ1-dominant cancers such as CESC, GBM, and HNSC showed a high correlation between CD59 and TGFβ1, leading to suppression of cytotoxic T cell activity. Conclusion: Overall, the correlation between CD59 and immune cells predicts its prognosis as unfavorable in CESC, GBM, HNSC, and STAD while being favorable in KIRC. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: Development of Cancer Research)
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15 pages, 2756 KiB  
Article
Tumor Immune Microenvironment Biomarkers for Recurrence Prediction in Locally Advanced Rectal Cancer Patients after Neoadjuvant Chemoradiotherapy
by Jun-Eul Hwang, Sung-Sun Kim, Hyun-Jin Bang, Hyeon-Jong Kim, Hyun-Jeong Shim, Woo-Kyun Bae, Ik-Joo Chung, Eun-Gene Sun, Taebum Lee, Chan-Young Ock, Jeong-Seok Nam and Sang-Hee Cho
Cancers 2024, 16(19), 3353; https://doi.org/10.3390/cancers16193353 - 30 Sep 2024
Viewed by 1037
Abstract
Background/Objectives: The tumor microenvironment (TME) has emerged as a significant prognostic factor. This study aimed to identify prognostic factors by combining clinicopathologic parameters and the TME biomarkers in patients who underwent surgery following neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC). Methods: [...] Read more.
Background/Objectives: The tumor microenvironment (TME) has emerged as a significant prognostic factor. This study aimed to identify prognostic factors by combining clinicopathologic parameters and the TME biomarkers in patients who underwent surgery following neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC). Methods: CD8+ T cells, CXCR3, CXCL10, and α-smooth muscle actin (α-SMA) were analyzed via immunohistochemical staining. We also incorporated AI-powered digital pathology to assess the spatial TME. The associations between these biomarkers, clinicopathologic parameters, and survival outcomes were evaluated. Results: CD8+ T cell expression, CXCR3 expression in tumor-infiltrating lymphocytes (TILs), and immune phenotypes were correlated. LARC patients with a high expression of CD8+ T cells, CXCR3 in TILs, and an inflamed phenotype had a significantly better prognosis than their counterparts did. In the multivariate analysis, the expression of CD8+ T cells and the inflamed/immune-excluded phenotype were significant tumor immune microenvironment (TiME) biomarkers for recurrence-free survival (RFS) but not for overall survival (OS). Notably, patients with the immune-desert phenotype had a poor prognosis regardless of pathologic stage, even if postoperative chemotherapy was administered (p < 0.001). Conclusions: CD8+ T cells and AI-powered immune phenotypes, alongside clinical factors, can guide personalized treatment in LARC patients receiving nCRT. A therapeutic strategy to modify the TiME after nCRT could help reduce recurrence after surgery. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: Development of Cancer Research)
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20 pages, 8614 KiB  
Article
CSF1R Ligands Expressed by Murine Gliomas Promote M-MDSCs to Suppress CD8+ T Cells in a NOS-Dependent Manner
by Gregory P. Takacs, Julia S. Garcia, Caitlyn A. Hodges, Christian J. Kreiger, Alexandra Sherman and Jeffrey K. Harrison
Cancers 2024, 16(17), 3055; https://doi.org/10.3390/cancers16173055 - 1 Sep 2024
Viewed by 1153
Abstract
Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that [...] Read more.
Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2+/CX3CR1+ M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2+/CX3CR1+ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma-secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in the M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that is driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: Development of Cancer Research)
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12 pages, 5298 KiB  
Article
A Mature Tertiary Lymphoid Structure with a Ki-67-Positive Proliferating Germinal Center Is Associated with a Good Prognosis and High Intratumoral Immune Cell Infiltration in Advanced Colorectal Cancer
by Natsumi Mori, Gendensuren Dorjkhorloo, Takuya Shiraishi, Bilguun Erkhem-Ochir, Haruka Okami, Arisa Yamaguchi, Ikuma Shioi, Chika Komine, Mizuki Endo, Takaomi Seki, Nobuhiro Hosoi, Nobuhiro Nakazawa, Yuta Shibasaki, Takuhisa Okada, Katsuya Osone, Akihiko Sano, Makoto Sakai, Makoto Sohda, Takehiko Yokobori, Ken Shirabe and Hiroshi Saekiadd Show full author list remove Hide full author list
Cancers 2024, 16(15), 2684; https://doi.org/10.3390/cancers16152684 - 28 Jul 2024
Viewed by 1309
Abstract
Tertiary lymphoid structures (TLSs) are complex lymphocyte clusters that arise in non-lymphoid tissues due to inflammation or cancer. A mature TLS with proliferating germinal centers is associated with a favorable prognosis in various cancers. However, the effect of TLS maturity on advanced colorectal [...] Read more.
Tertiary lymphoid structures (TLSs) are complex lymphocyte clusters that arise in non-lymphoid tissues due to inflammation or cancer. A mature TLS with proliferating germinal centers is associated with a favorable prognosis in various cancers. However, the effect of TLS maturity on advanced colorectal cancer (CRC) remains unexplored. We analyzed the significance of TLS maturity and tumor Ki-67 expression in surgically resected tumors from 78 patients with pathological T4 CRC. Mature TLS was defined as the organized infiltration of T and B cells with Ki-67-positive proliferating germinal centers. We analyzed the relationship between TLS maturity and intratumoral immune cell infiltration. Mature TLS with germinal center Ki-67 expression was associated with microsatellite instability and improved survival; however, high tumor Ki-67 expression was associated with poor survival in the same cohort. Multivariate analysis identified the absence of mature TLS as an independent predictor of poor post-recurrence overall survival. Intratumoral infiltration of T lymphocytes and macrophages was significantly elevated in tumors with mature TLS compared to those lacking it. High Ki-67 levels and absent mature TLS were identified as poor prognostic factors in advanced CRC. Mature TLS could serve as a promising marker for patients at high-risk of CRC. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: Development of Cancer Research)
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