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Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance: 2nd Edition

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

Deadline for manuscript submissions: 20 March 2025 | Viewed by 4854

Special Issue Editor

Dr. Jason Yongsheng Chan

E-Mail Website
Guest Editor
Department of Medical Oncology, National Cancer Centre Singapore | NCCS, Singapore, Singapore
Interests: rare cancers; lymphoma; biomarkers; translational research; genomics; spatial technologies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The field of cancer immunotherapy continues to excite basic scientific and translational research. From an oncologist’s perspective, immunotherapy has revolutionized contemporary cancer management, and is now considered a standard treatment option for many types of cancer. However, a major unmet need exists in that treatment resistance occurs in the vast majority of patients. A deeper understanding of tumor-intrinsic factors and their interplay with the tumor microenvironment has led to the identification of potential biomarkers of resistance and response, and has opened new avenues to improve upon existing treatment approaches. Moving forwards, it is anticipated that emerging innovative technologies that enable multi-dimensional, high-throughput and multiplex profiling will drive new discoveries in this aspect.

I cordially invite authors to submit original research and review articles to this Special Issue, which addresses the latest progress in and current understanding of complex mechanisms underlying responses and resistance to cancer immunotherapy.

In this Special Issue, experts in the field will review the latest research on the tumor microenvironment and its role in modulating immune resistance across various cancer types. Additionally, the topics will cover broad mechanisms of immunotherapy resistance and novel strategies to overcome them. It will also encourage research articles related to new predictive biomarkers and emerging therapeutic targets, as well as state-of-the-art technologies that accelerate studies in these areas.

Dr. Jason Yongsheng Chan
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.

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Keywords

  • cancer immunotherapy
  • tumor microenvironment
  • biomarkers
  • immune resistance
  • T cells
  • immune checkpoint
  • tumor-infiltrating lymphocytes
  • tumor mutational burden
  • dendritic cells
  • PD-L1

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Published Papers (3 papers)

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Research

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15 pages, 3576 KiB  
Article
High-Throughput Transcriptomics Identifies Chemoresistance-Associated Gene Expression Signatures in Human Angiosarcoma
by Glenys Mai Shia Khor, Sara Haghani, Tiffany Rui En Tan, Elizabeth Chun Yong Lee, Bavani Kannan, Boon Yee Lim, Jing Yi Lee, Zexi Guo, Tun Kiat Ko and Jason Yongsheng Chan
Int. J. Mol. Sci. 2024, 25(19), 10863; https://doi.org/10.3390/ijms251910863 - 9 Oct 2024
Viewed by 1029
Abstract
Angiosarcomas, clinically aggressive cancers of endothelial origin, are a rare subtype of soft-tissue sarcomas characterized by resistance to chemotherapy and dismal prognosis. In this study, we aim to identify the transcriptomic biomarkers of chemoresistance in angiosarcoma. We examined 72 cases of Asian angiosarcomas, [...] Read more.
Angiosarcomas, clinically aggressive cancers of endothelial origin, are a rare subtype of soft-tissue sarcomas characterized by resistance to chemotherapy and dismal prognosis. In this study, we aim to identify the transcriptomic biomarkers of chemoresistance in angiosarcoma. We examined 72 cases of Asian angiosarcomas, including 35 cases treated with palliative chemotherapy, integrating information from NanoString gene expression profiling, whole transcriptome profiling (RNA-seq), immunohistochemistry, cell line assays, and clinicopathological data. In the chemoresistant cohort (defined as stable disease or progression), we observed the significant overexpression of genes, including SPP1 (log2foldchange 3.49, adj. p = 0.0112), CXCL13, CD48, and CLEC5A, accompanied by the significant enrichment of myeloid compartment and cytokine and chemokine signaling pathways, as well as neutrophils and macrophages. RNA-seq data revealed higher SPP1 expression (p = 0.0008) in tumor tissues over adjacent normal compartments. Immunohistochemistry showed a significant moderate positive correlation between SPP1 protein and gene expression (r = 0.7016; p < 0.00110), while higher SPP1 protein expression correlated with lower chemotherapeutic sensitivity in patient-derived angiosarcoma cell lines MOLAS and ISOHAS. In addition, SPP1 mRNA overexpression positively correlated with epithelioid histology (p = 0.007), higher tumor grade (p = 0.0023), non-head and neck location (p = 0.0576), and poorer overall survival outcomes (HR 1.84, 95% CI 1.07–3.18, p = 0.0288). There was no association with tumor mutational burden, tumor inflammation signature, the presence of human herpesvirus-7, ultraviolet exposure signature, and metastatic state at diagnosis. In conclusion, SPP1 overexpression may be a biomarker of chemoresistance and poor prognosis in angiosarcoma. Further investigation is needed to uncover the precise roles and underlying mechanisms of SPP1. Full article
(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance: 2nd Edition)
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17 pages, 3055 KiB  
Article
A Comparison of Spatial and Phenotypic Immune Profiles of Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions
by Thomas Enzler, Jiaqi Shi, Jake McGue, Brian D. Griffith, Lei Sun, Vaibhav Sahai, Hari Nathan and Timothy L. Frankel
Int. J. Mol. Sci. 2024, 25(5), 2953; https://doi.org/10.3390/ijms25052953 - 3 Mar 2024
Cited by 1 | Viewed by 1675
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of 12.5%. PDAC predominantly arises from non-cystic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN). We used multiplex immunofluorescence and computational imaging technology to characterize, map, and [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of 12.5%. PDAC predominantly arises from non-cystic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN). We used multiplex immunofluorescence and computational imaging technology to characterize, map, and compare the immune microenvironments (IMEs) of PDAC and its precursor lesions. We demonstrate that the IME of IPMN was abundantly infiltrated with CD8+ T cells and PD-L1-positive antigen-presenting cells (APCs), whereas the IME of PanIN contained fewer CD8+ T cells and fewer PD-L1-positive APCs but elevated numbers of immunosuppressive regulatory T cells (Tregs). Thus, immunosuppression in IPMN and PanIN seems to be mediated by different mechanisms. While immunosuppression in IPMN is facilitated by PD-L1 expression on APCs, Tregs seem to play a key role in PanIN. Our findings suggest potential immunotherapeutic interventions for high-risk precursor lesions, namely, targeting PD-1/PD-L1 in IPMN and CTLA-4-positive Tregs in PanIN to restore immunosurveillance and prevent progression to cancer. Tregs accumulate with malignant transformation, as observed in PDAC, and to a lesser extent in IPMN-associated PDAC (IAPA). High numbers of Tregs in the microenvironment of PDAC went along with a markedly decreased interaction between CD8+ T cells and cancerous epithelial cells (ECs), highlighting the importance of Tregs as key players in immunosuppression in PDAC. We found evidence that a defect in antigen presentation, further aggravated by PD-L1 expression on APC, may contribute to immunosuppression in IAPA, suggesting a role for PD-L1/PD-1 immune checkpoint inhibitors in the treatment of IAPA. Full article
(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance: 2nd Edition)
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Review

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28 pages, 3925 KiB  
Review
Epidermal Growth Factor Receptor Targeting in Colorectal Carcinoma: Antibodies and Patient-Derived Organoids as a Smart Model to Study Therapy Resistance
by Samuele Tardito, Serena Matis, Maria Raffaella Zocchi, Roberto Benelli and Alessandro Poggi
Int. J. Mol. Sci. 2024, 25(13), 7131; https://doi.org/10.3390/ijms25137131 - 28 Jun 2024
Cited by 1 | Viewed by 1524
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Therefore, the need for new therapeutic strategies is still a challenge. Surgery and chemotherapy represent the first-line interventions; nevertheless, the prognosis for metastatic CRC (mCRC) patients remains unacceptable. An important step [...] Read more.
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Therefore, the need for new therapeutic strategies is still a challenge. Surgery and chemotherapy represent the first-line interventions; nevertheless, the prognosis for metastatic CRC (mCRC) patients remains unacceptable. An important step towards targeted therapy came from the inhibition of the epidermal growth factor receptor (EGFR) pathway, by the anti-EGFR antibody, Cetuximab, or by specific tyrosine kinase inhibitors (TKI). Cetuximab, a mouse–human chimeric monoclonal antibody (mAb), binds to the extracellular domain of EGFR thus impairing EGFR-mediated signaling and reducing cell proliferation. TKI can affect the EGFR biochemical pathway at different steps along the signaling cascade. Apart from Cetuximab, other anti-EGFR mAbs have been developed, such as Panitumumab. Both antibodies have been approved for the treatment of KRAS-NRAS wild type mCRC, alone or in combination with chemotherapy. These antibodies display strong differences in activating the host immune system against CRC, due to their different immunoglobulin isotypes. Although anti-EGFR antibodies are efficient, drug resistance occurs with high frequency. Resistant tumor cell populations can either already be present before therapy or develop later by biochemical adaptations or new genomic mutations in the EGFR pathway. Numerous efforts have been made to improve the efficacy of the anti-EGFR mAbs or to find new agents that are able to block downstream EGFR signaling cascade molecules. Indeed, we examined the importance of analyzing the anti-EGFR antibody–drug conjugates (ADC) developed to overcome resistance and/or stimulate the tumor host’s immunity against CRC growth. Also, patient-derived CRC organoid cultures represent a useful and feasible in vitro model to study tumor behavior and therapy response. Organoids can reflect tumor genetic heterogeneity found in the tissue of origin, representing a unique tool for personalized medicine. Thus, CRC-derived organoid cultures are a smart model for studying the tumor microenvironment and for the preclinical assay of anti-EGFR drugs. Full article
(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance: 2nd Edition)
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