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Cancers
Special Issues
Immunotherapy for Cancers
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Immunotherapy for Cancers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: 31 January 2025 | Viewed by 8768

Special Issue Editors

Dr. Antonino Bruno

E-Mail Website
Guest Editor
1. Laboratory of Immunology and General Pathology, University of Insubria, Varese, Italy
2. Laboratory of Innate Immunity, IRCCS MultiMedica, Milan, Italy
Interests: natural killer cells; innate lymphoid cells; tumor microenvironment; tumor angiogenesis; tumor immunology; immunotherapy
Special Issues, Collections and Topics in MDPI journals
Dr. Barbara Bassani

E-Mail Website
Guest Editor
Laboratory of Innate Immunity, IRCCS MultiMedica, Milan, Italy
Interests: natural killer cells; neutrophils; myeloid-derived suppressor cells; T cells; tumor immunology; mesenchymal cells; ZEB1; angiogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer immunotherapy is a revolutionary tool to fight against cancer, restoring/re-awakening the immune host response by different approaches including vaccines (including nano-vaccines), cell therapies (including CAR-T and, more recently, CAR-NK), modified antibodies, immunocytokines, etc.

Although immunotherapy has emerged as the “next generation” of cancer treatment, it has not yet been shown to be successful in the treatment of all cancer types, for whom the preferential therapeutic options still remain radiotherapy, chemotherapy, and target therapy. This strongly suggests that a deeper examination of the interactions between immune cells in the micro- and macro-environment, which are currently poorly characterized, is still crucial for the clinical outcome and success of immunotherapy.

From this perspective, the immune-tumor microenvironment (TIME), as a key element in the new era of immunotherapy, has become a major challenge, and reverting this in the case of resistance to immunotherapy is still a major challenge. During this time, the roles of tissue-residing cells in promoting or suppressing tumor growth, metastasis and resistance to therapy have been gradually elucidated. Immunotherapy presents an opportunity to fight against cancer; several strategies have been employed but not all are successful. It is therefore clear that in the “window of unsuccessful immunotherapy”, a deeper knowledge of cellular and molecular mechanisms regulating immune suppression and angiogenesis is still required. It is also now clear that immunotherapy alone is not sufficient to eliminate cancer, thus opening new windows for therapeutic approaches based on combinations (in term of molecules and timing/sequences of their administration).

For this Special Issue, we aim to collect original research, reviews, mini-reviews, and perspective articles reviewing/discussing the state of the art and/or proposing novel insights in basic and translational research of cancer immunotherapy. Areas of interest include but are not limited to:

  • High-throughput (“omics” and bioinformatic) approaches followed by experimental validation to dissect (novel) molecular targets for cancer immunotherapy;
  • TME/TIME-oriented molecular and cellular mechanisms/targets as potential candidates for immunotherapy;
  • The role of chronic inflammation and fibrosis in permitting immune-escape and/or resistance to immunotherapy;
  • Metabolic and immunometabolic drivers of immunosuppression, tumor progression/metastasis and resistance to cancer immunotherapy;
  • Combination approaches, including drug repurposing, in cancer immunotherapy;
  • Novel diagnostic or prognostic tools for cancer immunotherapy;
  • Stromal–immune cell interactions driving tumor progression, immunoescape and resistance to immunotherapy;
  • Epigenetics and immunotherapy;
  • Marine drugs and phytochemicals able to potentiate the immune response against cancers.

You may choose our Joint Special Issue in Vaccines.

Dr. Antonino Bruno
Dr. Barbara Bassani
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. 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

  • cancer immunotherapy
  • innate immunity
  • adaptive immunity
  • tumor immune microenvironment
  • tumor microenvironment
  • combination therapies
  • drug repurposing

Published Papers (7 papers)

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Research

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14 pages, 7237 KiB  
Article
Pre-Existing Immunity Predicts Response to First-Line Immunotherapy in Non-Small Cell Lung Cancer Patients
by Anastasia Xagara, Maria Goulielmaki, Sotirios P. Fortis, Alexandros Kokkalis, Evangelia Chantzara, George Christodoulopoulos, Ioannis Samaras, Emmanouil Saloustros, Konstantinos Tsapakidis, Vasileios Papadopoulos, Ioannis S. Pateras, Vasilis Georgoulias, Constantin N. Baxevanis and Athanasios Kotsakis
Cancers 2024, 16(13), 2393; https://doi.org/10.3390/cancers16132393 - 28 Jun 2024
Viewed by 472
Abstract
T-cell-mediated anti-tumoral responses may have significant clinical relevance as a biomarker for response to immunotherapy. The value of peripheral blood pre-existing tumor antigen-specific T cells (PreI+) as a predictive immunotherapy biomarker in NSCLC patients was investigated, along with the frequency of [...] Read more.
T-cell-mediated anti-tumoral responses may have significant clinical relevance as a biomarker for response to immunotherapy. The value of peripheral blood pre-existing tumor antigen-specific T cells (PreI+) as a predictive immunotherapy biomarker in NSCLC patients was investigated, along with the frequency of various circulating immune cells. Fifty-two treatment-naïve, stage III/IV NSCLC patients, treated with front-line immune checkpoint inhibitors (ICI)-containing regimens were enrolled. PreI was calculated as the percentages of CD3+IFNγ+ cells after in vitro co-cultures of PBMCs with peptides against four different Tumor-Associated Antigens (TAA). Immunophenotyping of peripheral blood immune cells was performed using multicolor flow cytometry. PreI+ T cells were detected in 44% of patients. Median overall survival (OS) was significantly higher in PreI+ patients compared to PreI– patients (not reached vs. 321 days, respectively; p = 0.014). PreI+ patients had significantly higher numbers of possible exhausted CD3+CD8+PD-1+ cells and lower percentages of immunosuppressive Tregs compared to PreI− patients. Additionally, patients with PreI+ and low numbers of peripheral blood M-MDSCs had a significant survival advantage compared to the rest of the patients. Thus, combining pre-existing tumor antigen-specific immunity before initiation of ICI in NSCLC patients with selected immune-suppressive cells could identify patients who have a favorable clinical outcome when treated with ICI-containing regimens. Full article
(This article belongs to the Special Issue Immunotherapy for Cancers)
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19 pages, 11920 KiB  
Article
Computational Approach for the Development of pH-Selective PD-1/PD-L1 Signaling Pathway Inhibition in Fight with Cancer
by Roderick C. McDowell, Jordhan D. Booth, Allyson McGowan, Wojciech Kolodziejczyk, Glake A. Hill, Santanu Banerjee, Manliang Feng and Karina Kapusta
Cancers 2024, 16(13), 2295; https://doi.org/10.3390/cancers16132295 - 22 Jun 2024
Viewed by 492
Abstract
Immunotherapy, particularly targeting the PD-1/PD-L1 pathway, holds promise in cancer treatment by regulating the immune response and preventing cancer cells from evading immune destruction. Nonetheless, this approach poses a risk of unwanted immune system activation against healthy cells. To minimize this risk, our [...] Read more.
Immunotherapy, particularly targeting the PD-1/PD-L1 pathway, holds promise in cancer treatment by regulating the immune response and preventing cancer cells from evading immune destruction. Nonetheless, this approach poses a risk of unwanted immune system activation against healthy cells. To minimize this risk, our study proposes a strategy based on selective targeting of the PD-L1 pathway within the acidic microenvironment of tumors. We employed in silico methods, such as virtual screening, molecular mechanics, and molecular dynamics simulations, analyzing approximately 10,000 natural compounds from the MolPort database to find potential hits with the desired properties. The simulations were conducted under two pH conditions (pH = 7.4 and 5.5) to mimic the environments of healthy and cancerous cells. The compound MolPort-001-742-690 emerged as a promising pH-selective inhibitor, showing a significant affinity for PD-L1 in acidic conditions and lower toxicity compared to known inhibitors like BMS-202 and LP23. A detailed 1000 ns molecular dynamics simulation confirmed the stability of the inhibitor-PD-L1 complex under acidic conditions. This research highlights the potential of using in silico techniques to discover novel pH-selective inhibitors, which, after experimental validation, may enhance the precision and reduce the toxicity of immunotherapies, offering a transformative approach to cancer treatment. Full article
(This article belongs to the Special Issue Immunotherapy for Cancers)
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12 pages, 861 KiB  
Article
Reactivation of Varicella-Zoster Virus in Patients with Lung Cancer Receiving Immune Checkpoint Inhibitors: Retrospective Nationwide Population-Based Cohort Study from South Korea
by Jiyun Jung, Seong-Yeon Park, Jae-Yoon Park, Dalyong Kim, Kyoungmin Lee and Sungim Choi
Cancers 2024, 16(8), 1499; https://doi.org/10.3390/cancers16081499 - 14 Apr 2024
Viewed by 999
Abstract
Background: This study aimed to determine the association between immune checkpoint inhibitors (ICIs) and the risk of herpes zoster (HZ) incidence in patients with lung cancer. Method: We obtained national claims data of 51,021 patients from South Korea with lung cancer between August [...] Read more.
Background: This study aimed to determine the association between immune checkpoint inhibitors (ICIs) and the risk of herpes zoster (HZ) incidence in patients with lung cancer. Method: We obtained national claims data of 51,021 patients from South Korea with lung cancer between August 2017 and December 2021. The study population was classified into ICI and non-ICI groups based on the prescription of ICIs at least once during the study period. To estimate the effects of ICIs treatment compared with those without ICIs treatment on HZ incidence, we used the Cox proportional hazards model adjusted for sex, age, comorbidities, and concomitant use of immunosuppressive drugs. Stratified analyses based on sex, age, and comorbidities were conducted to identify corresponding risk factors. Results: Of the 51,021 study participants, 897 (1.8%) were prescribed ICIs and 2262 (4.4%) were diagnosed with HZ. Approximately 75.6% of the patients receiving ICIs were male, and the prevalence of diabetes, cardiovascular disease, and chronic lung disease in the ICI group was significantly lower than that in the non-ICIs group. The Kaplan–Meier plot showed that the probability of incidence of HZ in the ICIs group was lower than that in the non-ICIs group. Additionally, treatment with ICIs was associated with a 31% lower incidence of developing HZ when compared to that seen without ICIs treatment (95% confidence interval [CI], 0.48–1.00). This association was stronger in females (hazard ratio [HR], 0.42; 95% CI, 0.19–0.94) and those less than 68 years of age (HR, 0.58; 95% CI, 0.34–0.99). Conclusions: In these real-world data from an Asian population with lung cancer, ICIs treatment might be associated with a reduced risk of HZ compared to that without ICIs treatment. Full article
(This article belongs to the Special Issue Immunotherapy for Cancers)
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11 pages, 3536 KiB  
Article
Induction of Immunological Antitumor Effects by the Combination of Adenovirus-Mediated Gene Transfer of B7-1 and Anti-Programmed Cell Death-1 Antibody in a Murine Squamous Cell Carcinoma Model
by Makiko Hara, Sumiyo Saburi, Natsumi Uehara, Takahiro Tsujikawa, Mie Kubo, Tatsuya Furukawa, Masanori Teshima, Hirotaka Shinomiya, Shigeru Hirano and Ken-ichi Nibu
Cancers 2024, 16(7), 1359; https://doi.org/10.3390/cancers16071359 - 30 Mar 2024
Viewed by 1727
Abstract
Background: The goal of this study was to evaluate the antitumor immune effects of B7-1 gene expression in addition to immune checkpoint inhibitor against squamous cell carcinoma. Methods: A murine SCC cell line, KLN205, was infected with adenoviral vector carrying B7-1 (AdB7). Infected [...] Read more.
Background: The goal of this study was to evaluate the antitumor immune effects of B7-1 gene expression in addition to immune checkpoint inhibitor against squamous cell carcinoma. Methods: A murine SCC cell line, KLN205, was infected with adenoviral vector carrying B7-1 (AdB7). Infected cells were injected subcutaneously in the flanks of DBA/2 mice. Three weeks after implantation, anti-mouse PD-1 antibody (antiPD1) was intraperitonially administrated twice a week for a total of six times. Results: CD80 was significantly overexpressed in the AdB7-infected tumors. IFN-gamma in the T cells in the spleen was significantly increased and tumor size was significantly reduced in the mice treated with both AdB7 and antiPD1. Targeted tumors treated with both AdB7 and antiPD1 exhibited significantly increased cell densities of total immune cells as well as Ki-67+ CD8+ T cells and decreased regulatory T cells. Conclusions: These results suggest that the B7-1 gene transfer may enhance the antitumor effect of anti-PD1 antibody against SCC. Full article
(This article belongs to the Special Issue Immunotherapy for Cancers)
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18 pages, 7854 KiB  
Article
The Defined TLR3 Agonist, Nexavant, Exhibits Anti-Cancer Efficacy and Potentiates Anti-PD-1 Antibody Therapy by Enhancing Immune Cell Infiltration
by Seung-Hwan Lee, Young-Ho Choi, Soon Myung Kang, Min-Gyu Lee, Arnaud Debin, Eric Perouzel, Seung-Beom Hong and Dong-Ho Kim
Cancers 2023, 15(24), 5752; https://doi.org/10.3390/cancers15245752 - 8 Dec 2023
Viewed by 1633
Abstract
Nexavant was reported as an alternative to the TLR3 agonist of Poly(I:C) and its derivatives. The physicochemical properties, signaling pathways, anti-cancer effects, and mechanisms of Nexavant were investigated. The distinctive characteristics of Nexavant compared to that of Poly(I:C) were demonstrated by precise quantification, [...] Read more.
Nexavant was reported as an alternative to the TLR3 agonist of Poly(I:C) and its derivatives. The physicochemical properties, signaling pathways, anti-cancer effects, and mechanisms of Nexavant were investigated. The distinctive characteristics of Nexavant compared to that of Poly(I:C) were demonstrated by precise quantification, enhanced thermostability, and increased resistance to RNase A. Unlike Poly(I:C), which activates TLR3, RIG-I, and MDA5, Nexavant stimulates signaling through TLR3 and RIG-I but not through MDA5. Compared to Poly(I:C), an intratumoral Nexavant treatment led to a unique immune response, immune cell infiltration, and suppression of tumor growth in various animal cancer models. Nexavant therapy outperformed anti-PD-1 antibody treatment in all the tested models and showed a synergistic effect in combinational therapy, especially in well-defined cold tumor models. The effect was similar to that of nivolumab in a humanized mouse model. Intranasal instillation of Nexavant led to the recruitment of immune cells (NK, CD4+ T, and CD8+ T) to the lungs, suppressing lung metastasis and improving animal survival. Our study highlighted Nexavant’s defined nature for clinical use and unique signaling pathways and its potential as a standalone anti-cancer agent or in combination with anti-PD-1 antibodies. Full article
(This article belongs to the Special Issue Immunotherapy for Cancers)
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45 pages, 8055 KiB  
Article
HIV-1 Protease as DNA Immunogen against Drug Resistance in HIV-1 Infection: DNA Immunization with Drug Resistant HIV-1 Protease Protects Mice from Challenge with Protease-Expressing Cells
by Stefan Petkov, Athina Kilpeläinen, Ekaterina Bayurova, Anastasia Latanova, Dzeina Mezale, Ilse Fridrihsone, Elizaveta Starodubova, Juris Jansons, Alesja Dudorova, Ilya Gordeychuk, Britta Wahren and Maria Isaguliants
Cancers 2023, 15(1), 238; https://doi.org/10.3390/cancers15010238 - 30 Dec 2022
Cited by 3 | Viewed by 1973
Abstract
DNA immunization with HIV-1 protease (PR) is advanced for immunotherapy of HIV-1 infection to reduce the number of infected cells producing drug-resistant virus. A consensus PR of the HIV-1 FSU_A strain was designed, expression-optimized, inactivated (D25N), and supplemented with drug resistance (DR) mutations [...] Read more.
DNA immunization with HIV-1 protease (PR) is advanced for immunotherapy of HIV-1 infection to reduce the number of infected cells producing drug-resistant virus. A consensus PR of the HIV-1 FSU_A strain was designed, expression-optimized, inactivated (D25N), and supplemented with drug resistance (DR) mutations M46I, I54V, and V82A common for FSU_A. PR variants with D25N/M46I/I54V (PR_Ai2mut) and with D25N/M46I/I54V/V82A (PR_Ai3mut) were cloned into the DNA vaccine vector pVAX1, and PR_Ai3mut, into a lentiviral vector for the transduction of murine mammary adenocarcinoma cells expressing luciferase 4T1luc2. BALB/c mice were DNA-immunized by intradermal injections of PR_Ai, PR_Ai2mut, PR_Ai3mut, vector pVAX1, or PBS with electroporation. All PR variants induced specific CD8+ T-cell responses revealed after splenocyte stimulation with PR-derived peptides. Splenocytes of mice DNA-immunized with PR_Ai and PR_Ai2mut were not activated by peptides carrying V82A, whereas splenocytes of PR_Ai3mut-immunized mice recognized both peptides with and without V82A mutation. Mutations M46I and I54V were immunologically silent. In the challenge study, DNA immunization with PR_Ai3mut protected mice from the outgrowth of subcutaneously implanted adenocarcinoma 4T1luc2 cells expressing PR_Ai3mut; a tumor was formed only in 1/10 implantation sites and no metastases were detected. Immunizations with other PR variants were not protective; all mice formed tumors and multiple metastasis in the lungs, liver, and spleen. CD8+ cells of PR_Ai3mut DNA-immunized mice exhibited strong IFN-γ/IL-2 responses against PR peptides, while the splenocytes of mice in other groups were nonresponsive. Thus, immunization with a DNA plasmid encoding inactive HIV-1 protease with DR mutations suppressed the growth and metastatic activity of tumor cells expressing PR identical to the one encoded by the immunogen. This demonstrates the capacity of T-cell response induced by DNA immunization to recognize single DR mutations, and supports the concept of the development of immunotherapies against drug resistance in HIV-1 infection. It also suggests that HIV-1-infected patients developing drug resistance may have a reduced natural immune response against DR HIV-1 mutations causing an immune escape. Full article
(This article belongs to the Special Issue Immunotherapy for Cancers)
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Review

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40 pages, 3503 KiB  
Review
Contemporary Approaches to Immunotherapy of Solid Tumors
by Alla V. Kuznetsova, Xenia A. Glukhova, Olga P. Popova, Igor P. Beletsky and Alexey A. Ivanov
Cancers 2024, 16(12), 2270; https://doi.org/10.3390/cancers16122270 - 19 Jun 2024
Viewed by 920
Abstract
In recent years, the arrival of the immunotherapy industry has introduced the possibility of providing transformative, durable, and potentially curative outcomes for various forms of malignancies. However, further research has shown that there are a number of issues that significantly reduce the effectiveness [...] Read more.
In recent years, the arrival of the immunotherapy industry has introduced the possibility of providing transformative, durable, and potentially curative outcomes for various forms of malignancies. However, further research has shown that there are a number of issues that significantly reduce the effectiveness of immunotherapy, especially in solid tumors. First of all, these problems are related to the protective mechanisms of the tumor and its microenvironment. Currently, major efforts are focused on overcoming protective mechanisms by using different adoptive cell therapy variants and modifications of genetically engineered constructs. In addition, a complex workforce is required to develop and implement these treatments. To overcome these significant challenges, innovative strategies and approaches are necessary to engineer more powerful variations of immunotherapy with improved antitumor activity and decreased toxicity. In this review, we discuss recent innovations in immunotherapy aimed at improving clinical efficacy in solid tumors, as well as strategies to overcome the limitations of various immunotherapies. Full article
(This article belongs to the Special Issue Immunotherapy for Cancers)
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