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Molecular and Cellular Advances in the Tumor Microenvironment and Cancer Immunotherapy

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: 31 August 2024 | Viewed by 3382

Special Issue Editor

Dr. Cristina Belgiovine

E-Mail Website
Guest Editor
Department of Clinical, Surgical, Diagnostics and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy
Interests: immune microenvironment; tumor; advanced cellular therapy; immunotherapy; tumor associated macrophages

Special Issue Information

Dear Colleagues,

In recent years, significant molecular advances have been made in our understanding of the tumor microenvironment and its role in cancer immunotherapy. The tumor microenvironment encompasses the cellular and molecular components surrounding a tumor, including immune cells, fibroblasts, blood vessels, and the extracellular matrix. Researchers have discovered that the tumor microenvironment plays a crucial role in regulating tumor growth, invasion, and response to therapy. By studying molecular interactions within the tumor microenvironment, scientists have identified several key pathways and molecules that can be targeted for cancer immunotherapy.

For instance, immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4 inhibitors, have been developed to block inhibitory signals that cancer cells exploit to evade immune surveillance. Moreover, researchers are investigating the role of various immune cells, including T cells, natural killer cells, and myeloid-derived suppressor cells, in the tumor microenvironment to develop novel immunotherapeutic strategies.

These molecular advances have opened up new avenues for cancer treatment and have demonstrated promising results in clinical trials. By targeting specific molecules and pathways within the tumor microenvironment, immunotherapies aim to activate and enhance the body's immune system to recognize and eliminate cancer cells.

This Special Issue aims to gather original works and reviews dedicated to the molecular understanding of the tumor microenvironment. Its primary objectives are to increase knowledge about the efficacy of immunotherapy, to explore immunotherapy resistance mechanisms, to study combined approaches to simultaneously target multiple pathways, and to highlight success stories in improving patient outcomes in the fight against cancer.

Dr. Cristina Belgiovine
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. 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

  • tumor microenvironment
  • tumor infiltrated leukocytes
  • immunotherapy
  • targeted therapy
  • immune checkpoint inhibitor

Published Papers (5 papers)

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Research

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12 pages, 3292 KiB  
Article
Spatial Distribution of Macrophage and Lymphocyte Subtypes within Tumor Microenvironment to Predict Recurrence of Non-Muscle-Invasive Papillary Urothelial Carcinoma after BCG Immunotherapy
by Julius Drachneris, Mindaugas Morkunas, Mantas Fabijonavicius, Albertas Cekauskas, Feliksas Jankevicius and Arvydas Laurinavicius
Int. J. Mol. Sci. 2024, 25(9), 4776; https://doi.org/10.3390/ijms25094776 (registering DOI) - 27 Apr 2024
Viewed by 249
Abstract
Non-muscle-invasive papillary urothelial carcinoma (NMIPUC) of the urinary bladder is the most common type of bladder cancer. Intravesical Bacille Calmette–Guerin (BCG) immunotherapy is applied in patients with a high risk of recurrence and progression of NMIPUC to muscle-invasive disease. However, the tumor relapses [...] Read more.
Non-muscle-invasive papillary urothelial carcinoma (NMIPUC) of the urinary bladder is the most common type of bladder cancer. Intravesical Bacille Calmette–Guerin (BCG) immunotherapy is applied in patients with a high risk of recurrence and progression of NMIPUC to muscle-invasive disease. However, the tumor relapses in about 30% of patients despite the treatment, raising the need for better risk stratification. We explored the potential of spatial distributions of immune cell subtypes (CD20, CD11c, CD163, ICOS, and CD8) within the tumor microenvironment to predict NMIPUC recurrence following BCG immunotherapy. Based on analyses of digital whole-slide images, we assessed the densities of the immune cells in the epithelial–stromal interface zone compartments and their distribution, represented by an epithelial–stromal interface density ratio (IDR). While the densities of any cell type did not predict recurrence, a higher IDR of CD11c (HR: 0.0012, p-value = 0.0002), CD8 (HR: 0.0379, p-value = 0.005), and ICOS (HR: 0.0768, p-value = 0.0388) was associated with longer recurrence-free survival (RFS) based on the univariate Cox regression. The history of positive repeated TUR (re-TUR) (HR: 4.93, p-value = 0.0001) and T1 tumor stage (HR: 2.04, p-value = 0.0159) were associated with shorter RFS, while G3 tumor grade according to the 1973 WHO classification showed borderline significance (HR: 1.83, p-value = 0.0522). In a multivariate analysis, the two models with a concordance index exceeding 0.7 included the CD11c IDR in combination with either a history of positive re-TUR or tumor stage. We conclude that the CD11c IDR is the most informative predictor of NMIPUC recurrence after BCG immunotherapy. Our findings highlight the importance of assessment of the spatial distribution of immune cells in the tumor microenvironment. Full article
(This article belongs to the Special Issue Molecular and Cellular Advances in the Tumor Microenvironment and Cancer Immunotherapy)
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22 pages, 10980 KiB  
Article
Upregulation of EMR1 (ADGRE1) by Tumor-Associated Macrophages Promotes Colon Cancer Progression by Activating the JAK2/STAT1,3 Signaling Pathway in Tumor Cells
by Rokeya Akter, Rackhyun Park, Soo Kyung Lee, Eun ju Han, Kyu-Sang Park, Junsoo Park and Mee-Yon Cho
Int. J. Mol. Sci. 2024, 25(8), 4388; https://doi.org/10.3390/ijms25084388 - 16 Apr 2024
Viewed by 371
Abstract
Previously, we reported that epidermal growth factor-like module-containing mucin-like hormone receptor-like 1 (EMR1/ADGRE1) is abnormally expressed in colon cancer (CC) and is a risk factor for lymph node metastasis (LNM) and poor recurrence-free survival in patients with abundant tumor-associated macrophages (TAMs). However, the [...] Read more.
Previously, we reported that epidermal growth factor-like module-containing mucin-like hormone receptor-like 1 (EMR1/ADGRE1) is abnormally expressed in colon cancer (CC) and is a risk factor for lymph node metastasis (LNM) and poor recurrence-free survival in patients with abundant tumor-associated macrophages (TAMs). However, the signaling pathways associated with EMR1 expression in CC progression remain unclear. In this study, we aimed to explore the role of EMR1 and its signaling interactions with macrophages in CC progression. Spatial transcriptomics of pT3 microsatellite unstable CC tissues revealed heightened Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling in EMR1-HL CC with LNM compared to EMR1-N CC without LNM. Through in vitro coculture of CC cells with macrophages, EMR1 expression by CC cells was found to be induced by TAMs, ultimately interacting with upregulated JAK/STAT signaling, increasing cell proliferation, migration, and motility, and reducing apoptosis. JAK2/STAT3 inhibition decreased the levels of EMR1, JAK2, STAT1, and STAT3, significantly impeded the proliferation, migration, and mobility of cells, and increased the apoptosis of EMR1+ CC cells compared to their EMR1KO counterparts. Overall, TAMs-induced EMR1 upregulation in CC cells may promote LNM and CC progression via JAK2/STAT1,3 signaling upregulation. This study provides further insights into the molecular mechanisms involving macrophages and intracellular EMR1 expression in CC progression, suggesting its clinical significance and offering potential interventions to enhance patient outcomes. Full article
(This article belongs to the Special Issue Molecular and Cellular Advances in the Tumor Microenvironment and Cancer Immunotherapy)
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13 pages, 3990 KiB  
Article
In Silico Transcriptomic Expression of MSR1 in Solid Tumors Is Associated with Responses to Anti-PD1 and Anti-CTLA4 Therapies
by Adrián Sanvicente, Cristina Díaz-Tejeiro, Cristina Nieto-Jiménez, Lucia Paniagua-Herranz, Igor López Cade, Győrffy Balázs, Víctor Moreno, Pedro Pérez-Segura, Emiliano Calvo and Alberto Ocaña
Int. J. Mol. Sci. 2024, 25(7), 3987; https://doi.org/10.3390/ijms25073987 - 03 Apr 2024
Viewed by 515
Abstract
Immuno-oncology has gained momentum with the approval of antibodies with clinical activities in different indications. Unfortunately, for anti-PD (L)1 agents in monotherapy, only half of the treated population achieves a clinical response. For other agents, such as anti-CTLA4 antibodies, no biomarkers exist, and [...] Read more.
Immuno-oncology has gained momentum with the approval of antibodies with clinical activities in different indications. Unfortunately, for anti-PD (L)1 agents in monotherapy, only half of the treated population achieves a clinical response. For other agents, such as anti-CTLA4 antibodies, no biomarkers exist, and tolerability can limit administration. In this study, using publicly available genomic datasets, we evaluated the expression of the macrophage scavenger receptor-A (SR-A) (MSR1) and its association with a response to check-point inhibitors (CPI). MSR1 was associated with the presence of macrophages, dendritic cells (DCs) and neutrophils in most of the studied indications. The presence of MSR1 was associated with macrophages with a pro-tumoral phenotype and correlated with TIM3 expression. MSR1 predicted favorable overall survival in patients treated with anti-PD1 (HR: 0.56, FDR: 1%, p = 2.6 × 10−5), anti PD-L1 (HR: 0.66, FDR: 20%, p = 0.00098) and anti-CTLA4 (HR: 0.37, FDR: 1%, p = 4.8 × 10−5). When specifically studying skin cutaneous melanoma (SKCM), we observed similar effects for anti-PD1 (HR: 0.65, FDR: 50%, p = 0.0072) and anti-CTLA4 (HR: 0.35, FDR: 1%, p = 4.1 × 10−5). In a different dataset of SKCM patients, the expression of MSR1 predicted a clinical response to anti-CTLA4 (AUC: 0.61, p = 2.9 × 10−2). Here, we describe the expression of MSR1 in some solid tumors and its association with innate cells and M2 phenotype macrophages. Of note, the presence of MSR1 predicted a response to CPI and, particularly, anti-CTLA4 therapies in different cohorts of patients. Future studies should prospectively explore the association of MSR1 expression and the response to anti-CTLA4 strategies in solid tumors. Full article
(This article belongs to the Special Issue Molecular and Cellular Advances in the Tumor Microenvironment and Cancer Immunotherapy)
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Review

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26 pages, 2010 KiB  
Review
Car T Cells in Solid Tumors: Overcoming Obstacles
by Joselyn Rojas-Quintero, María P. Díaz, Jim Palmar, Nataly J. Galan-Freyle, Valery Morillo, Daniel Escalona, Henry J. González-Torres, Wheeler Torres, Elkin Navarro-Quiroz, Diego Rivera-Porras and Valmore Bermúdez
Int. J. Mol. Sci. 2024, 25(8), 4170; https://doi.org/10.3390/ijms25084170 - 10 Apr 2024
Viewed by 545
Abstract
Chimeric antigen receptor T cell (CAR T cell) therapy has emerged as a prominent adoptive cell therapy and a therapeutic approach of great interest in the fight against cancer. This approach has shown notorious efficacy in refractory hematological neoplasm, which has bolstered its [...] Read more.
Chimeric antigen receptor T cell (CAR T cell) therapy has emerged as a prominent adoptive cell therapy and a therapeutic approach of great interest in the fight against cancer. This approach has shown notorious efficacy in refractory hematological neoplasm, which has bolstered its exploration in the field of solid cancers. However, successfully managing solid tumors presents considerable intrinsic challenges, which include the necessity of guiding the modified cells toward the tumoral region, assuring their penetration and survival in adverse microenvironments, and addressing the complexity of identifying the specific antigens for each type of cancer. This review focuses on outlining the challenges faced by CAR T cell therapy when used in the treatment of solid tumors, as well as presenting optimizations and emergent approaches directed at improving its efficacy in this particular context. From precise localization to the modulation of the tumoral microenvironment and the adaptation of antigen recognition strategies, diverse pathways will be examined to overcome the current limitations and buttress the therapeutic potential of CAR T cells in the fight against solid tumors. Full article
(This article belongs to the Special Issue Molecular and Cellular Advances in the Tumor Microenvironment and Cancer Immunotherapy)
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14 pages, 727 KiB  
Review
Targeting the Tumor Microenvironment in Breast Cancer: Prognostic and Predictive Significance and Therapeutic Opportunities
by María A. Domínguez-Cejudo, Ana Gil-Torralvo, Mónica Cejuela, Sonia Molina-Pinelo and Javier Salvador Bofill
Int. J. Mol. Sci. 2023, 24(23), 16771; https://doi.org/10.3390/ijms242316771 - 26 Nov 2023
Viewed by 982
Abstract
Breast cancer is one of the most prevalent tumors among women. Its prognosis and treatment outcomes depend on factors related to tumor cell biology. However, recent studies have revealed the critical role of the tumor microenvironment (TME) in the development, progression, and treatment [...] Read more.
Breast cancer is one of the most prevalent tumors among women. Its prognosis and treatment outcomes depend on factors related to tumor cell biology. However, recent studies have revealed the critical role of the tumor microenvironment (TME) in the development, progression, and treatment response of breast cancer. In this review, we explore the different components of the TME and their relevance as prognostic and predictive biomarkers in breast cancer. In addition, techniques for assessing the tumor microenvironment, such as immunohistochemistry or gene expression profiling, and their clinical utility in therapeutic decision-making are examined. Finally, therapeutic strategies targeting the TME are reviewed, highlighting their potential clinical benefits. Overall, this review emphasizes the importance of the TME in breast cancer and its potential as a clinical tool for better patient stratification and the design of personalized therapies. Full article
(This article belongs to the Special Issue Molecular and Cellular Advances in the Tumor Microenvironment and Cancer Immunotherapy)
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