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Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 3.0
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Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 3.0

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: closed (30 August 2023) | Viewed by 10881

Special Issue Editor

Prof. Dr. Donald J. Buchsbaum

E-Mail Website
Guest Editor
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Interests: cancer immunotherapy; radioimmunotherapy; monoclonal antibody therapy; targeting cancer stem cells; TRAIL-DR5 therapy; Wnt/β-catenin inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

This Special Issue is the continuation of our 2019 Special Issue, “Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions” and 2021 Special Issue “Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0”.

Immune checkpoints are regulators of the immune system. Checkpoint inhibitor monoclonal antibodies that block CTLA-4 or PD1/PD-L1 have been approved for the treatment of several cancers including melanoma, bladder, and lung cancer. Despite increases in overall survival, not all patients respond to treatment. Approaches to increase survival include the use of new checkpoint inhibitors to regulate T cell responses and other immune effectors, identification of predictive biomarkers, modulators of the immune response, and the use of combination immunotherapies and therapies. This Special Issue will incorporate, but is not limited to, the following sub-topics:

  • Novel checkpoints and inhibitors
  • Immune checkpoint activators
  • Immune regulation
  • Biomarkers predictive of response
  • Immunomodulatory agents including cytokines
  • Targeting of innate immunity
  • Adaptive immunity
  • Neoantigen targeted therapies
  • T cell exhaustion
  • Targeting of immunosuppressive cells
  • Mechanisms of tumor immune cell evasion
  • Modulation of the immunosuppressive tumor microenvironment
  • Targeting Wnt ligand signaling

Prof. Dr. Donald J. Buchsbaum
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

  • cancer immunotherapy
  • checkpoint inhibitors
  • innate immunity
  • adaptive immunity
  • immunosuppression
  • immunomodulation

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Published Papers (3 papers)

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Research

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17 pages, 2657 KiB  
Article
Persistent TLR4 Activation Promotes Hepatocellular Carcinoma Growth through Positive Feedback Regulation by LIN28A/Let-7g miRNA
by I-Ting Chen, An-Chieh Cheng, Yi-Ting Liu, Chieh Yan, Yi-Chen Cheng, Chiung-Fang Chang and Ping-Hui Tseng
Int. J. Mol. Sci. 2022, 23(15), 8419; https://doi.org/10.3390/ijms23158419 - 29 Jul 2022
Cited by 11 | Viewed by 2349
Abstract
Chronic inflammation caused by liver damage or infection plays an important role in the development and progression of hepatocellular carcinoma (HCC). The activation of Toll-like receptors 4 (TLR4) is involved in HCC tumorigenesis. Moreover, high TLR4 expression in HCC has been linked to [...] Read more.
Chronic inflammation caused by liver damage or infection plays an important role in the development and progression of hepatocellular carcinoma (HCC). The activation of Toll-like receptors 4 (TLR4) is involved in HCC tumorigenesis. Moreover, high TLR4 expression in HCC has been linked to poor prognosis. Although the expression of TLR4 in HCC is relatively low compared to hematopoietic cells, it is important to explore the molecular mechanism leading to the elevation of TLR4 in HCC. In this study, we aimed to investigate the positive regulating loop for TLR4 expression in HCC in response to chronic inflammation. Our results confirm that the mRNA expression of TLR4 and proinflammatory cytokines, including interleukin 6 (IL6) and C-C motif chemokine ligand 2 (CCL2), positively correlate in human HCC samples. High TLR4 expression in HCC is more susceptible to lipopolysaccharide (LPS); TLR4 activation in HCC provides growth and survival advantages and thus promotes tumorigenesis. It has been shown that the LIN28/let-7 microRNA (miRNA) axis is a downstream effector of the TLR4 signal pathway, and let-7 miRNA is a potential post-transcriptional regulator for TLR4. Thus, we investigated the correlation between TLR4 and LIN28A mRNA and let-7g miRNA in HCC clinical samples and found that the expression of TLR4 was positively correlated with LIN28A and negatively correlated with let-7g miRNA. Moreover, by culturing PLC/PRF5 (PLC5) HCC cells in low-dose LPS-containing medium to mimic chronic inflammation for persistent TLR4 activation, the mRNA and protein levels of TLR4 and LIN28A were elevated, and let-7g miRNA was decreased. Furthermore, the 3’ untranslated region (3’UTR) of TLR4 mRNA was shown to be the target of let-7g miRNA, suggesting that inhibition of let-7g miRNA is able to increase TLR4 mRNA. While parental PLC5 cells have a low susceptibility to LPS-induced cell growth, long-term LPS exposure for PLC5 cells leads to increased proliferation, cytokine expression and stemness properties. In conclusion, our studies demonstrate positive feedback regulation for chronic TLR4 activation in the modulation of TLR4 expression level through the LIN28A/let-7g pathway in HCC and suggest a connection between chronic inflammation and TLR4 expression level in HCC for promoting tumorigenesis. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 3.0)
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Review

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28 pages, 5882 KiB  
Review
Role of Next Generation Immune Checkpoint Inhibitor (ICI) Therapy in Philadelphia Negative Classic Myeloproliferative Neoplasm (MPN): Review of the Literature
by Ruchi Yadav, Narek Hakobyan and Jen-Chin Wang
Int. J. Mol. Sci. 2023, 24(15), 12502; https://doi.org/10.3390/ijms241512502 - 7 Aug 2023
Cited by 3 | Viewed by 3431
Abstract
The Philadelphia chromosome-negative (Ph−) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are enduring and well-known conditions. These disorders are characterized by the abnormal growth of one or more hematopoietic cell lineages in the body’s stem cells, [...] Read more.
The Philadelphia chromosome-negative (Ph−) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are enduring and well-known conditions. These disorders are characterized by the abnormal growth of one or more hematopoietic cell lineages in the body’s stem cells, leading to the enlargement of organs and the manifestation of constitutional symptoms. Numerous studies have provided evidence indicating that the pathogenesis of these diseases involves the dysregulation of the immune system and the presence of chronic inflammation, both of which are significant factors. Lately, the treatment of cancer including hematological malignancy has progressed on the agents aiming for the immune system, cytokine environment, immunotherapy agents, and targeted immune therapy. Immune checkpoints are the molecules that regulate T cell function in the tumor microenvironment (TME). The first line of primary immune checkpoints are programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Immune checkpoint inhibitor therapy (ICIT) exerts its anti-tumor actions by blocking the inhibitory pathways in T cells and has reformed cancer treatment. Despite the impressive clinical success of ICIT, tumor internal resistance poses a challenge for oncologists leading to a low response rate in solid tumors and hematological malignancies. A Phase II trial on nivolumab for patients with post-essential thrombocythemia myelofibrosis, primary myelofibrosis, or post-polycythemia myelofibrosis was performed (Identifier: NCT02421354). This trial tested the efficacy of a PD-1 blockade agent, namely nivolumab, but was terminated prematurely due to adverse events and lack of efficacy. A multicenter, Phase II, single-arm open-label study was conducted including pembrolizumab in patients with primary thrombocythemia, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. This study showed that pembrolizumab treatment did not have many adverse events, but there were no pertinent clinical responses hence it was terminated after the first stage was completed. To avail the benefits from immunotherapy, the paradigm has shifted to new immune checkpoints in the TME such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain immunoglobulin-containing suppressor of T cell activation (VISTA), and human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) forming the basis of next-generation ICIT. The primary aim of this article is to underscore and elucidate the significance of next-generation ICIT in the context of MPN. Specifically, we aim to explore the potential of monoclonal antibodies as targeted immunotherapy and the development of vaccines targeting specific MPN epitopes, with the intent of augmenting tumor-related immune responses. It is anticipated that these therapeutic modalities rooted in immunotherapy will not only expand but also enhance the existing treatment regimens for patients afflicted with MPN. Preliminary studies from our laboratory showed over-expressed MDSC and over-expressed VISTA in MDSC, and in progenitor and immune cells directing the need for more clinical trials using next-generation ICI in the treatment of MPN. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 3.0)
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12 pages, 773 KiB  
Review
Adjuvant Therapy for Renal Cell Carcinoma: Hype or Hope?
by Federica Cosso, Giandomenico Roviello, Gabriella Nesi, Sonia Shabani, Pietro Spatafora, Donata Villari and Martina Catalano
Int. J. Mol. Sci. 2023, 24(4), 4243; https://doi.org/10.3390/ijms24044243 - 20 Feb 2023
Cited by 9 | Viewed by 4165
Abstract
Renal cell carcinoma (RCC) is the third most common genitourinary cancer accounting for approximately 180,000 deaths worldwide in 2020. Although over two-thirds of patients initially present localized disease, up to 50% of them may progress to metastatic disease. Adjuvant therapy aims to reduce [...] Read more.
Renal cell carcinoma (RCC) is the third most common genitourinary cancer accounting for approximately 180,000 deaths worldwide in 2020. Although over two-thirds of patients initially present localized disease, up to 50% of them may progress to metastatic disease. Adjuvant therapy aims to reduce the recurrence risk and improve outcomes in several types of cancers but is currently an unmet need in RCC. The results achieved with tyrosine kinase inhibitors in metastatic RCC led to the evaluation of these target therapies in an early setting with conflicting results for disease-free survival and no overall survival (OS) benefit. Likewise, the results of immune checkpoint inhibitors (ICIs) in an adjuvant setting are conflicting. Available data did not show an improvement in OS with ICIs in the early phase, although a positive trend for pembrolizumab has been recorded, receiving the Food and Drug Administration’s approval in this setting. However, the disappointing results of several ICIs and the heterogeneous pattern of RCC warrant biomarker identification and subgroup analyses to evaluate which patients could benefit from adjuvant therapy. In this review, we will discuss the rationale for adjuvant treatment in RCC, summarizing the results of the most important adjuvant therapy trials and current applications, to outline possible future directions. Full article
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 3.0)
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