Editorial Board Members’ Collection Series: Utilization of Immune Checkpoint Inhibitors: Past, Present and Future Therapeutics in Cancer

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 14791

Special Issue Editors


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Guest Editor
Department of Pharmacology & Physiology, School of Biomedical Science, Oklahoma State University Center for Health Sciences, Tulsa, OK 74107-1898, USA
Interests: pancreatic cancer; environmental toxicants; mitochondrial toxicity; apoptosis; cellular regulation; tryptophan-kynurenine pathway; indoleamine 2,3-dioxygenase
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Guest Editor
Department of Internal Medicine, University of Genoa, Genoa, Italy
Interests: immunodeficiency; immune-mediated diseases; biologics; pharmacogenomics; vaccines
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The focus on immune checkpoint involvement in the development of cancer has increased dramatically over the last decade. Dysfunctions in these pathways, leading to excessive activation, inhibits the cells’ normal response to damage, leading to unchecked cellular growth. Early pathways, such as the programmed cell death receptor (PD-1) or the cytotoxic lymphocyte-associated molecule-4 (CTLA-4) involved inhibition of the pathway to slow tumor growth. More recent, some checkpoint pathways require stimulation to exert anti-tumor actions. These pathways include CD40 and OX40 pathways. Modifying the tumor microenvironment, thus interfering with cellular energy production and utilization, has become another area of intense interest. Modifying the activity of the tryptophan–kynurenine pathway, and its rate-limiting step, indoleamine 2,3-dioxygenase enzyme has been explored as a potential target of anti-cancer drugs via the inhibition of the indoleamine 2,3-dioxygenase isozymes. The goal of the series is to provide a collection of review and original articles that describe the work that has been done and the outlook for therapeutic developments that target immune checkpoints to attenuate or block cancer development.

Prof. Dr. David R. Wallace
Dr. Giuseppe Murdaca
Guest Editors

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Keywords

  • cytotoxic T-cell
  • PD-1/PD-L1
  • indoleamine 2,3-dioxygenase
  • apoptosis
  • PI3K
  • β-catenin
  • biomarkers
  • tumor microenvironment
  • mTOR
  • immunotherapy

Published Papers (5 papers)

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Research

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18 pages, 4751 KiB  
Article
Immunohistochemical Detection of Estrogen Receptor-Beta (ERβ) with PPZ0506 Antibody in Murine Tissue: From Pitfalls to Optimization
by Sarah K. Schröder, Carmen G. Tag, Jan C. Kessel, Per Antonson and Ralf Weiskirchen
Biomedicines 2022, 10(12), 3100; https://doi.org/10.3390/biomedicines10123100 - 1 Dec 2022
Cited by 6 | Viewed by 1636
Abstract
The estrogen receptor beta (ERβ) is physiologically essential for reproductive biology and is implicated in various diseases. However, despite more than 20 years of intensive research on ERβ, there are still uncertainties about its distribution in tissues and cellular expression. Several studies show [...] Read more.
The estrogen receptor beta (ERβ) is physiologically essential for reproductive biology and is implicated in various diseases. However, despite more than 20 years of intensive research on ERβ, there are still uncertainties about its distribution in tissues and cellular expression. Several studies show contrasts between mRNA and protein levels, and the use of knockout strategies revealed that many commercially available antibodies gave false-positive expression results. Recently, a specific monoclonal antibody against human ERβ (PPZ0506) showed cross-reactivity with rodents and was optimized for the detection of rat ERβ. Herein, we established an immunohistochemical detection protocol for ERβ protein in mouse tissue. Staining was optimized on murine ovaries, as granulosa cells are known to strongly express ERβ. The staining results were confirmed by western blot analysis and RT-PCR. To obtain accurate and reliable staining results, different staining conditions were tested in paraffin-embedded tissues. Different pitfalls were encountered in immunohistochemical detection. Strong heat-induced epitope retrieval (HIER) and appropriate antibody dilution were required to visualize specific nuclear expression of ERβ. Finally, the specificity of the antibody was confirmed by using ovaries from Esr2-depleted mice. However, in some animals, strong (non-specific) background staining appeared. These signals could not be significantly alleviated with commercially available additional blocking solutions and are most likely due to estrus-dependent expression of endogenous immunoglobulins. In summary, our study showed that the antibody PPZ0506, originally directed against human ERβ, is also suitable for reliable detection of murine ERβ. An established staining protocol mitigated ambiguities regarding the expression and distribution of ERβ in different tissues and will contribute to an improved understanding of its role and functions in murine tissues in the future. Full article
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Review

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24 pages, 790 KiB  
Review
Checkpoint Inhibitors in Acute Myeloid Leukemia
by Daniela Damiani and Mario Tiribelli
Biomedicines 2023, 11(6), 1724; https://doi.org/10.3390/biomedicines11061724 - 15 Jun 2023
Cited by 2 | Viewed by 2315
Abstract
The prognosis of acute myeloid leukemia (AML) remains unsatisfactory. Among the reasons for the poor response to therapy and high incidence of relapse, there is tumor cell immune escape, as AML blasts can negatively influence various components of the immune system, mostly weakening [...] Read more.
The prognosis of acute myeloid leukemia (AML) remains unsatisfactory. Among the reasons for the poor response to therapy and high incidence of relapse, there is tumor cell immune escape, as AML blasts can negatively influence various components of the immune system, mostly weakening T-cells. Since leukemic cells can dysregulate immune checkpoints (ICs), receptor-based signal transductors that lead to the negative regulation of T-cells and, eventually, to immune surveillance escape, the inhibition of ICs is a promising therapeutic strategy and has led to the development of so-called immune checkpoint inhibitors (ICIs). ICIs, in combination with conventional chemotherapy, hypomethylating agents or targeted therapies, are being increasingly tested in cases of AML, but the results reported are often conflicting. Here, we review the main issues concerning the immune system in AML, the main pathways leading to immune escape and the results obtained from clinical trials of ICIs, alone or in combination, in newly diagnosed or relapsed/refractory AML. Full article
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12 pages, 995 KiB  
Review
Checkpoint Inhibitor-Induced Colitis: An Update
by Giuseppe Losurdo, Daniele Angelillo, Nicolas Favia, Maria Chiara Sergi, Alfredo Di Leo, Giacomo Triggiano and Marco Tucci
Biomedicines 2023, 11(5), 1496; https://doi.org/10.3390/biomedicines11051496 - 22 May 2023
Cited by 5 | Viewed by 5540
Abstract
Immunotherapy with immune checkpoint inhibitors (ICIs) nowadays has indications for several solid tumors. The current targets for ICIs are CTLA-4, PD-1, and PD-L1 receptors. Despite the clinical advantages derived from ICIs, a variety of side effects are linked to overstimulation of the immune [...] Read more.
Immunotherapy with immune checkpoint inhibitors (ICIs) nowadays has indications for several solid tumors. The current targets for ICIs are CTLA-4, PD-1, and PD-L1 receptors. Despite the clinical advantages derived from ICIs, a variety of side effects are linked to overstimulation of the immune system. Among these, ICI-related colitis is one of the most common, with a disabling impact on the patient. Diarrhea, abdominal pain, abdominal distension, cramping, and hematochezia are the most common ICI enterocolitis presenting symptoms. The most frequently used grading system for assessment of the severity of ICI enterocolitis is called the Common Terminology Criteria for Adverse Events (CTCAE) grading. With regard to the histological picture, there is no specific feature; however, microscopic damage can be classified into five types: (1) acute active colitis, (2) chronic active colitis, (3) microscopic colitis-like, (4) graft-versus-host disease-like, and (5) other types. Supportive therapy (oral hydration, a bland diet without lactose or caffeine, and anti-diarrheal agents) is indicated in mild colitis. Symptomatic treatment alone or with loperamide, a low-fiber diet, and spasmolytics are recommended for low-grade diarrhea. In more severe cases, corticosteroid treatment is mandatory. In refractory cases, off-label use of biological therapies (infliximab or vedolizumab) was proposed. Full article
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32 pages, 1924 KiB  
Review
Redox Signaling Modulates Activity of Immune Checkpoint Inhibitors in Cancer Patients
by Alessandro Allegra, Giuseppe Murdaca, Giuseppe Mirabile and Sebastiano Gangemi
Biomedicines 2023, 11(5), 1325; https://doi.org/10.3390/biomedicines11051325 - 29 Apr 2023
Cited by 1 | Viewed by 1962
Abstract
Although immunotherapy is already a staple of cancer care, many patients may not benefit from these cutting-edge treatments. A crucial field of research now focuses on figuring out how to improve treatment efficacy and assess the resistance mechanisms underlying this uneven response. For [...] Read more.
Although immunotherapy is already a staple of cancer care, many patients may not benefit from these cutting-edge treatments. A crucial field of research now focuses on figuring out how to improve treatment efficacy and assess the resistance mechanisms underlying this uneven response. For a good response, immune-based treatments, in particular immune checkpoint inhibitors, rely on a strong infiltration of T cells into the tumour microenvironment. The severe metabolic environment that immune cells must endure can drastically reduce effector activity. These immune dysregulation-related tumour-mediated perturbations include oxidative stress, which can encourage lipid peroxidation, ER stress, and T regulatory cells dysfunction. In this review, we have made an effort to characterize the status of immunological checkpoints, the degree of oxidative stress, and the part that latter plays in determining the therapeutic impact of immunological check point inhibitors in different neoplastic diseases. In the second section of the review, we will make an effort to assess new therapeutic possibilities that, by affecting redox signalling, may modify the effectiveness of immunological treatment. Full article
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16 pages, 1414 KiB  
Review
Immune Checkpoint Inhibitors in Renal Cell Carcinoma: Molecular Basis and Rationale for Their Use in Clinical Practice
by Francesco Lasorsa, Nicola Antonio di Meo, Monica Rutigliano, Martina Milella, Matteo Ferro, Savio Domenico Pandolfo, Felice Crocetto, Octavian Sabin Tataru, Riccardo Autorino, Michele Battaglia, Pasquale Ditonno and Giuseppe Lucarelli
Biomedicines 2023, 11(4), 1071; https://doi.org/10.3390/biomedicines11041071 - 2 Apr 2023
Cited by 43 | Viewed by 2853
Abstract
Renal cell carcinoma (RCC) is the seventh most common cancer in men and the ninth most common cancer in women worldwide. There is plenty of evidence about the role of the immune system in surveillance against tumors. Thanks to a better understanding of [...] Read more.
Renal cell carcinoma (RCC) is the seventh most common cancer in men and the ninth most common cancer in women worldwide. There is plenty of evidence about the role of the immune system in surveillance against tumors. Thanks to a better understanding of immunosurveillance mechanisms, immunotherapy has been introduced as a promising cancer treatment in recent years. Renal cell carcinoma (RCC) has long been thought chemoresistant but highly immunogenic. Considering that up to 30% of the patients present metastatic disease at diagnosis, and around 20–30% of patients undergoing surgery will suffer recurrence, we need to identify novel therapeutic targets. The introduction of immune checkpoint inhibitors (ICIs) in the clinical management of RCC has revolutionized the therapeutic approach against this tumor. Several clinical trials have shown that therapy with ICIs in combination or ICIs and the tyrosine kinase inhibitor has a very good response rate. In this review article we summarize the mechanisms of immunity modulation and immune checkpoints in RCC and discuss the potential therapeutic strategies in renal cancer treatment. Full article
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