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Advances in Immunotherapy for Cancer: From Molecular Basis to Novel Biomarkers and Therapeutic Targets

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 12628

Special Issue Editors

Dr. Valentina Audrito

E-Mail Website
Guest Editor
Department of Science and Technological Innovation DISIT, University of Eastern Piedmont, 15121 Alessandria, Italy
Interests: malignant melanoma; metabolic reprogramming; tumor microenvironment; metabolic cross-talk; NAD; NAMPT; immunotherapy; biomarker; therapy resistance
Special Issues, Collections and Topics in MDPI journals
Dr. Laura Conti

E-Mail Website
Guest Editor
Molecular Biotechnology Center "Guido Tarone", Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy
Interests: breast cancer; cancer vaccines; cancer immunotherapy; tumor microenvironment; microbiota; cancer stem cells; tumor antigens

Special Issue Information

Dear Colleagues,

We are delighted to announce that the Special Issue entitled “Advances in Immunotherapy for Cancer: From Molecular Basis to Novel Biomarkers and Therapeutic Targets” is now open to receiving proposals.

Despite remarkable advances in the field of immunotherapy have improved patient survival, cancer mortality due to therapy resistance and metastatic spread still represents an unsolved problem. Current studies demonstrate that a deeper understanding of molecular, metabolic, functional cross-talk between cancer and immune cells within the tumor microenvironment would be central to ameliorating patients’ outcomes.

To this aim, in this Special Issue for IJMS, we will focus on the most recent advances in the field of cancer immunotherapy, with a focus on the discovery of new targets and biomarkers and on tumor microenvironment, addressing how alterations to its molecular and metabolic features impact the response to immunotherapy. Such knowledge could represent the basis for the rational design of new immunotherapeutic and combined strategies for cancer patients’ treatment and for the identification of novel predictive biomarkers to monitor patients’ immune responses.

For IJMS's paper, nontargeted syntheses and studies with no molecular aspects are out of the scope. Clinical trials and animal and cell testings are eligible only if they are strongly needed to support hypotheses or theories concerning structure–function correlations and are not suitable if no molecular aspects are considered.

We invite basic and clinical investigators to present their valuable work either as original articles or reviews to this Special Issue. We would be very grateful for your contributions and consider it a pleasure to receive your manuscripts.

Potential topics include, but are not limited to:

  • Mechanisms of immunesuppression and immune escape;
  • Fuctional cross-talk between tumor and immune cells within tumor microenvironment: metabolic signals, soluble molecules;
  • Novel agents that regulate immune response;
  • Immunotherapy: clinical and biological effects and limits;
  • Metabolic and molecular mechanisms of resistance to immunotherapy;
  • Future perspective for immune checkpoint inhibitors;
  • Novel predictive biomarkers of therapy response;
  • Novel targets to be used in combination with immunotherapy;
  • Cancer vaccination;
  • Tumor antigens.

Dr. Valentina Audrito
Dr. Laura Conti
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

  • tumor microenvironment
  • immune suppression
  • metabolic and molecular mechanisms of resistance to therapy
  • tumor immune escape
  • immunotherapy
  • immune checkpoint inhibitors
  • cancer vaccination
  • tumor-infiltrating cells
  • biomarkers
  • tumor antigens
  • cancer metabolism

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Published Papers (6 papers)

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Research

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13 pages, 5345 KiB  
Article
Targeting Myeloid Cells in Head and Neck Squamous Cell Carcinoma: A Kinase Inhibitor Library Screening Approach
by Mohamed Y. Zaky, Jessy John, Monika Vashisht, Priya Singh, Mohammad A. I. Al-Hatamleh, Karen Siddoway, Zhangguo Chen and Jing H. Wang
Int. J. Mol. Sci. 2024, 25(22), 12277; https://doi.org/10.3390/ijms252212277 - 15 Nov 2024
Viewed by 389
Abstract
Head and neck squamous cell carcinoma (HNSCC) is highly enriched with tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). However, effective therapeutic agents targeting tumor-associated myeloid cells in HNSCC are currently lacking. Here, we employed a unique co-culture system [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is highly enriched with tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). However, effective therapeutic agents targeting tumor-associated myeloid cells in HNSCC are currently lacking. Here, we employed a unique co-culture system to investigate how HNSCC cells affect tumor-associated myeloid cells. We found that the presence of cancer cells significantly enhances myeloid cell proliferation and promotes TAM differentiation. To identify potential therapeutic agents, we screened a custom library of 70 kinase inhibitors to assess their effects on distinct subsets of tumor-associated myeloid cells. We discovered specific inhibitors that differentially suppressed the populations of TAMs, monocytic MDSCs (M-MDSCs), or polymorphonuclear MDSCs (PMN-MDSCs), suggesting that inhibiting different targets could reduce distinct subsets of tumor-associated myeloid cells. Conversely, some inhibitors were found to increase the population of CD11b+Ly6G−Ly6C− myeloid cells. Among the promising inhibitors tested, vatalanib, a VEGF-R inhibitor, demonstrated significant in vivo efficacy at inhibiting tumor growth and reducing tumor-associated myeloid cells, thereby underscoring its potential as a therapeutic agent. Our findings highlight specific kinase inhibitors with differential modulatory effects on HNSCC-associated myeloid subsets and caution the application of some as anti-cancer drugs. This experimental system may provide a robust platform for identifying new agents targeting tumor-associated myeloid cells in HNSCC and beyond, and for elucidating mechanistic insights into tumor-myeloid cell interaction. Full article
(This article belongs to the Special Issue Advances in Immunotherapy for Cancer: From Molecular Basis to Novel Biomarkers and Therapeutic Targets)
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22 pages, 4953 KiB  
Article
Macrophage Profiling in Head and Neck Cancer to Improve Patient Prognosis and Assessment of Cancer Cell–Macrophage Interactions Using Three-Dimensional Coculture Models
by Nour Mhaidly, Fabrice Journe, Ahmad Najem, Louis Stock, Anne Trelcat, Didier Dequanter, Sven Saussez and Géraldine Descamps
Int. J. Mol. Sci. 2023, 24(16), 12813; https://doi.org/10.3390/ijms241612813 - 15 Aug 2023
Cited by 3 | Viewed by 1874
Abstract
Tumor-associated macrophages are key components of the tumor microenvironment and play important roles in the progression of head and neck cancer, leading to the development of effective strategies targeting immune cells in tumors. Our study demonstrated the prognostic potential of a new scoring [...] Read more.
Tumor-associated macrophages are key components of the tumor microenvironment and play important roles in the progression of head and neck cancer, leading to the development of effective strategies targeting immune cells in tumors. Our study demonstrated the prognostic potential of a new scoring system (Macroscore) based on the combination of the ratio and the sum of the high and low densities of M1 (CD80+) and M2 (CD163+) macrophages in a series of head and neck cancer patients, including a training population (n = 54) and a validation population (n = 19). Interestingly, the Macroscore outperformed TNM criteria and p16 status, showing a significant association with poor patient prognosis, and demonstrated significant predictive value for overall survival. Additionally, 3D coculture spheroids were established to analyze the crosstalk between cancer cells and monocytes/macrophages. Our data revealed that cancer cells can induce monocyte differentiation into protumoral M2 macrophages, creating an immunosuppressive microenvironment. This coculture also induced the production of immunosuppressive cytokines, such as IL10 and IL8, known to promote M2 polarization. Finally, we validated the ability of the macrophage subpopulations to induce apoptosis (M1) or support proliferation (M2) of cancer cells. Overall, our research highlights the potential of the Macroscore as a valuable prognostic biomarker to enhance the clinical management of patients and underscores the relevance of a spheroid model in gaining a better understanding of the mechanisms underlying cancer cell–macrophage interactions. Full article
(This article belongs to the Special Issue Advances in Immunotherapy for Cancer: From Molecular Basis to Novel Biomarkers and Therapeutic Targets)
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17 pages, 1372 KiB  
Article
Exome-Based Genomic Markers Could Improve Prediction of Checkpoint Inhibitor Efficacy Independently of Tumor Type
by Lorraine Dalens, Julie Lecuelle, Laure Favier, Cléa Fraisse, Aurélie Lagrange, Courèche Kaderbhai, Romain Boidot, Sandy Chevrier, Hugo Mananet, Valentin Derangère, Caroline Truntzer and François Ghiringhelli
Int. J. Mol. Sci. 2023, 24(8), 7592; https://doi.org/10.3390/ijms24087592 - 20 Apr 2023
Cited by 3 | Viewed by 1901
Abstract
Immune checkpoint inhibitors (ICIs) have improved the care of patients in multiple cancer types. However, PD-L1 status, high Tumor Mutational Burden (TMB), and mismatch repair deficiency are the only validated biomarkers of efficacy for ICIs. These markers remain imperfect, and new predictive markers [...] Read more.
Immune checkpoint inhibitors (ICIs) have improved the care of patients in multiple cancer types. However, PD-L1 status, high Tumor Mutational Burden (TMB), and mismatch repair deficiency are the only validated biomarkers of efficacy for ICIs. These markers remain imperfect, and new predictive markers represent an unmet medical need. Whole-exome sequencing was carried out on 154 metastatic or locally advanced cancers from different tumor types treated by immunotherapy. Clinical and genomic features were investigated using Cox regression models to explore their capacity to predict progression-free survival (PFS). The cohort was split into training and validation sets to assess validity of observations. Two predictive models were estimated using clinical and exome-derived variables, respectively. Stage at diagnosis, surgery before immunotherapy, number of lines before immunotherapy, pleuroperitoneal, bone or lung metastasis, and immune-related toxicity were selected to generate a clinical score. KRAS mutations, TMB, TCR clonality, and Shannon entropy were retained to generate an exome-derived score. The addition of the exome-derived score improved the prediction of prognosis compared with the clinical score alone. Exome-derived variables could be used to predict responses to ICI independently of tumor type and might be of value in improving patient selection for ICI therapy. Full article
(This article belongs to the Special Issue Advances in Immunotherapy for Cancer: From Molecular Basis to Novel Biomarkers and Therapeutic Targets)
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Review

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23 pages, 5564 KiB  
Review
Innate Immune Cells in Melanoma: Implications for Immunotherapy
by Marialuisa Trocchia, Annagioia Ventrici, Luca Modestino, Leonardo Cristinziano, Anne Lise Ferrara, Francesco Palestra, Stefania Loffredo, Mariaelena Capone, Gabriele Madonna, Marilena Romanelli, Paolo Antonio Ascierto and Maria Rosaria Galdiero
Int. J. Mol. Sci. 2024, 25(15), 8523; https://doi.org/10.3390/ijms25158523 - 5 Aug 2024
Cited by 1 | Viewed by 1351
Abstract
The innate immune system, composed of neutrophils, basophils, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, dendritic cells (DCs), mast cells (MCs), and innate lymphoid cells (ILCs), is the first line of defense. Growing evidence demonstrates the crucial role of innate immunity in tumor initiation [...] Read more.
The innate immune system, composed of neutrophils, basophils, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, dendritic cells (DCs), mast cells (MCs), and innate lymphoid cells (ILCs), is the first line of defense. Growing evidence demonstrates the crucial role of innate immunity in tumor initiation and progression. Several studies support the idea that innate immunity, through the release of pro- and/or anti-inflammatory cytokines and tumor growth factors, plays a significant role in the pathogenesis, progression, and prognosis of cutaneous malignant melanoma (MM). Cutaneous melanoma is the most common skin cancer, with an incidence that rapidly increased in recent decades. Melanoma is a highly immunogenic tumor, due to its high mutational burden. The metastatic form retains a high mortality. The advent of immunotherapy revolutionized the therapeutic approach to this tumor and significantly ameliorated the patients’ clinical outcome. In this review, we will recapitulate the multiple roles of innate immune cells in melanoma and the related implications for immunotherapy. Full article
(This article belongs to the Special Issue Advances in Immunotherapy for Cancer: From Molecular Basis to Novel Biomarkers and Therapeutic Targets)
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17 pages, 1633 KiB  
Review
The Role of the Toll-like Receptor 2 and the cGAS-STING Pathways in Breast Cancer: Friends or Foes?
by Chiara Cossu, Antonino Di Lorenzo, Irene Fiorilla, Alberto Maria Todesco, Valentina Audrito and Laura Conti
Int. J. Mol. Sci. 2024, 25(1), 456; https://doi.org/10.3390/ijms25010456 - 29 Dec 2023
Cited by 2 | Viewed by 2144
Abstract
Breast cancer stands as a primary malignancy among women, ranking second in global cancer-related deaths. Despite treatment advancements, many patients progress to metastatic stages, posing a significant therapeutic challenge. Current therapies primarily target cancer cells, overlooking their intricate interactions with the tumor microenvironment [...] Read more.
Breast cancer stands as a primary malignancy among women, ranking second in global cancer-related deaths. Despite treatment advancements, many patients progress to metastatic stages, posing a significant therapeutic challenge. Current therapies primarily target cancer cells, overlooking their intricate interactions with the tumor microenvironment (TME) that fuel progression and treatment resistance. Dysregulated innate immunity in breast cancer triggers chronic inflammation, fostering cancer development and therapy resistance. Innate immune pattern recognition receptors (PRRs) have emerged as crucial regulators of the immune response as well as of several immune-mediated or cancer cell-intrinsic mechanisms that either inhibit or promote tumor progression. In particular, several studies showed that the Toll-like receptor 2 (TLR2) and the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathways play a central role in breast cancer progression. In this review, we present a comprehensive overview of the role of TLR2 and STING in breast cancer, and we explore the potential to target these PRRs for drug development. This information will significantly impact the scientific discussion on the use of PRR agonists or inhibitors in cancer therapy, opening up new and promising avenues for breast cancer treatment. Full article
(This article belongs to the Special Issue Advances in Immunotherapy for Cancer: From Molecular Basis to Novel Biomarkers and Therapeutic Targets)
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21 pages, 409 KiB  
Review
Virus-like Particle (VLP) Vaccines for Cancer Immunotherapy
by Francesca Ruzzi, Maria Sofia Semprini, Laura Scalambra, Arianna Palladini, Stefania Angelicola, Chiara Cappello, Olga Maria Pittino, Patrizia Nanni and Pier-Luigi Lollini
Int. J. Mol. Sci. 2023, 24(16), 12963; https://doi.org/10.3390/ijms241612963 - 19 Aug 2023
Cited by 11 | Viewed by 4112
Abstract
Cancer vaccines are increasingly being studied as a possible strategy to prevent and treat cancers. While several prophylactic vaccines for virus-caused cancers are approved and efficiently used worldwide, the development of therapeutic cancer vaccines needs to be further implemented. Virus-like particles (VLPs) are [...] Read more.
Cancer vaccines are increasingly being studied as a possible strategy to prevent and treat cancers. While several prophylactic vaccines for virus-caused cancers are approved and efficiently used worldwide, the development of therapeutic cancer vaccines needs to be further implemented. Virus-like particles (VLPs) are self-assembled protein structures that mimic native viruses or bacteriophages but lack the replicative material. VLP platforms are designed to display single or multiple antigens with a high-density pattern, which can trigger both cellular and humoral responses. The aim of this review is to provide a comprehensive overview of preventive VLP-based vaccines currently approved worldwide against HBV and HPV infections or under evaluation to prevent virus-caused cancers. Furthermore, preclinical and early clinical data on prophylactic and therapeutic VLP-based cancer vaccines were summarized with a focus on HER-2-positive breast cancer. Full article
(This article belongs to the Special Issue Advances in Immunotherapy for Cancer: From Molecular Basis to Novel Biomarkers and Therapeutic Targets)
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