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Cells
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Inhibiting Immune Checkpoint-Expressing Cells for Tumor Therapy
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Inhibiting Immune Checkpoint-Expressing Cells for Tumor Therapy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (15 August 2023) | Viewed by 40928

Special Issue Editor

Dr. Fabrizio Marcucci

E-Mail Website
Guest Editor
Department of Pharmacological and Biomolecular Sciences, University of Milan, via Trentacoste 2, 20134 Milan, Italy
Interests: Epithelial-mesenchymal transition (EMT); cancer stem-like cells (CSC); autophagy; antitumor immunity; drug delivery

Special Issue Information

Dear Colleagues,

Using monoclonal antibodies (mAb) against inhibitory immune checkpoint molecules (ICPM), referred to as immune checkpoint inhibitors (ICI), has become a mainstay in cancer therapy over the last decade. The main therapeutic effect of ICIs is thought to be the consequence of the inhibition of immunosuppression that derives from the interaction between ICPM ligands and receptors and, consequently, to the induction or reinduction of antitumor immune responses.

Several ICIs in clinical use have been engineered to be devoid of effector functions that may lead to the depletion of ICPM+ immune cells, thereby giving rise to an undesired inhibition of antitumor immune responses. In recent years, however, it has become clear that ICPMs are often overexpressed on a sizable fraction of tumor cells of different tumor types, and these tumor cells display an aggressive phenotype. Moreover, immune cells that express ICPMs are often endowed with immunosuppressive and/or immune-deviating functionalities. Therefore, depletion of ICPM+ tumor cells or immune cells may not be necessarily a drawback but may even be a desirable biological effect.

This Special Issue aims to present research on state-of-the-art developments in the field of ICI research and development, including both ICI that have been mainly designed to interfere with the interaction between ICPM ligands and receptors, as well as ICIs with the potential to deplete ICPM-expressing tumor cells or immune cells. Contributors are invited to address innovative approaches in this field, including approaches aimed at enhancing biological activity or modulating the expression of ICPMs in tumor cells and/or immune cells in order to improve the therapeutic efficacy of ICIs or non-antibody based ICI compounds with therapeutic potential.

Dr. Fabrizio Marcucci
Guest Editor

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Keywords

  • Immune checkpoint molecules
  • Depletion
  • EMT
  • Immunosuppression
  • Antibodies
  • Antibody-drug conjugates
  • CAR T cells
  • Effector functions

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Published Papers (9 papers)

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Research

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20 pages, 4070 KiB  
Article
Potent and Targeted Sindbis Virus Platform for Immunotherapy of Ovarian Cancer
by Silvana Opp, Alicia Hurtado, Christine Pampeno, Ziyan Lin and Daniel Meruelo
Cells 2023, 12(1), 77; https://doi.org/10.3390/cells12010077 - 24 Dec 2022
Cited by 6 | Viewed by 2321
Abstract
Our laboratory has been developing a Sindbis viral (SV) vector platform for treatments of ovarian and other types of cancers. In this study we show that SV.IL-12 combined with an agonistic OX40 antibody can eliminate ovarian cancer in a Mouse Ovarian Surface Epithelial [...] Read more.
Our laboratory has been developing a Sindbis viral (SV) vector platform for treatments of ovarian and other types of cancers. In this study we show that SV.IL-12 combined with an agonistic OX40 antibody can eliminate ovarian cancer in a Mouse Ovarian Surface Epithelial Cell Line (MOSEC) model and further prevent tumors in mice rechallenged with tumor cells after approximately 5 months. Treatment efficacy is shown to be dependent upon T-cells that are transcriptionally and metabolically reprogramed. An influx of immune cells to the tumor microenvironment occurs. Combination of sequences encoding both IL-12 and anti-OX40 into a single SV vector, SV.IgGOX40.IL-12, facilitates the local delivery of immunoregulatory agents to tumors enhancing the anti-tumor response. We promote SV.IgGOX40.IL-12 as a safe and effective therapy for multiple types of cancer. Full article
(This article belongs to the Special Issue Inhibiting Immune Checkpoint-Expressing Cells for Tumor Therapy)
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17 pages, 7205 KiB  
Article
The Fairy Chemical Imidazole-4-carboxamide Inhibits the Expression of Axl, PD-L1, and PD-L2 and Improves Response to Cisplatin in Melanoma
by Chisa Inoue, Taro Yasuma, Corina N. D’Alessandro-Gabazza, Masaaki Toda, Valeria Fridman D’Alessandro, Ryo Inoue, Hajime Fujimoto, Hajime Kobori, Suphachai Tharavecharak, Atsuro Takeshita, Kota Nishihama, Yuko Okano, Jing Wu, Tetsu Kobayashi, Yutaka Yano, Hirokazu Kawagishi and Esteban C. Gabazza
Cells 2022, 11(3), 374; https://doi.org/10.3390/cells11030374 - 22 Jan 2022
Cited by 9 | Viewed by 3516
Abstract
The leading cause of death worldwide is cancer. Many reports have proved the beneficial effect of mushrooms in cancer. However, the precise mechanism is not completely clear. In the present study, we focused on the medicinal properties of biomolecules released by fairy ring-forming [...] Read more.
The leading cause of death worldwide is cancer. Many reports have proved the beneficial effect of mushrooms in cancer. However, the precise mechanism is not completely clear. In the present study, we focused on the medicinal properties of biomolecules released by fairy ring-forming mushrooms. Fairy chemicals generally stimulate or inhibit the growth of surrounding vegetation. In the present study, we evaluated whether fairy chemicals (2-azahypoxanthine, 2-aza-8-oxohypoxanthine, and imidazole-4-carboxamide) exert anticancer activity by decreasing the expression of Axl and immune checkpoint molecules in melanoma cells. We used B16F10 melanoma cell lines and a melanoma xenograft model in the experiments. Treatment of melanoma xenograft with cisplatin combined with imidazole-4-carboxamide significantly decreased the tumor volume compared to untreated mice or mice treated cisplatin alone. In addition, mice treated with cisplatin and imidazole-4-carboxamide showed increased peritumoral infiltration of T cells compared to mice treated with cisplatin alone. In vitro studies showed that all fairy chemicals, including imidazole-4-carboxamide, inhibit the expression of immune checkpoint molecules and Axl compared to controls. Imidazole-4-carboxamide also significantly blocks the cisplatin-induced upregulation of PD-L1. These observations point to the fairy chemical imidazole-4-carboxamide as a promising coadjuvant therapy with cisplatin in patients with cancer. Full article
(This article belongs to the Special Issue Inhibiting Immune Checkpoint-Expressing Cells for Tumor Therapy)
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19 pages, 5336 KiB  
Article
Cell-Free DNA Variant Sequencing Using Plasma and AR-V7 Testing of Circulating Tumor Cells in Prostate Cancer Patients
by Verena Lieb, Amer Abdulrahman, Katrin Weigelt, Siegfried Hauch, Michael Gombert, Juan Guzman, Laura Bellut, Peter J. Goebell, Robert Stöhr, Arndt Hartmann, Bernd Wullich, Helge Taubert and Sven Wach
Cells 2021, 10(11), 3223; https://doi.org/10.3390/cells10113223 - 18 Nov 2021
Cited by 4 | Viewed by 2802
Abstract
Prostate cancer (PCa) is the second most common malignant cancer and is a major cause of morbidity and mortality among men worldwide. There is still an urgent need for biomarkers applicable for diagnosis, prognosis, therapy prediction, or therapy monitoring in PCa. Liquid biopsies, [...] Read more.
Prostate cancer (PCa) is the second most common malignant cancer and is a major cause of morbidity and mortality among men worldwide. There is still an urgent need for biomarkers applicable for diagnosis, prognosis, therapy prediction, or therapy monitoring in PCa. Liquid biopsies, including cell-free DNA (cfDNA) and circulating tumor cells (CTCs), are a valuable source for studying such biomarkers and are minimally invasive. In our study, we investigated the cfDNA of 34 progressive PCa patients, via targeted sequencing, for sequence variants and for the occurrence of CTCs, with a focus on androgen receptor splice variant 7 (AR-V7)-positive CTCs. The cfDNA content was associated with overall survival (OS; p = 0.014), disease-specific survival (DSS; p = 0.004), and time to treatment change (TTC; p = 0.001). Moreover, when considering all sequence variants grouped by their functional impact and allele frequency, a significant association with TTC (p = 0.017) was observed. When investigating only pathogenic or likely pathogenic gene variants, variants of the BRCA1 gene (p = 0.029) and the AR ligand-binding domain (p = 0.050) were associated with a shorter TTC. Likewise, the presence of CTCs was associated with a shorter TTC (p = 0.031). The presence of AR-V7-positive CTCs was associated with TTC (p < 0.001) in Kaplan–Meier analysis. Interestingly, all patients with AR-V7-positive CTCs also carried TP53 point mutations. Altogether, analysis of cfDNA and CTCs can provide complementary information that may support temporal and targeted treatment decisions and may elucidate the optimal choice within the variety of therapy options for advanced PCa patients. Full article
(This article belongs to the Special Issue Inhibiting Immune Checkpoint-Expressing Cells for Tumor Therapy)
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Review

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12 pages, 721 KiB  
Review
Targeting PIM Kinases to Improve the Efficacy of Immunotherapy
by Amber N. Clements and Noel A. Warfel
Cells 2022, 11(22), 3700; https://doi.org/10.3390/cells11223700 - 21 Nov 2022
Cited by 8 | Viewed by 2910
Abstract
The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases is a family of serine/threonine kinases that regulates numerous signaling networks that promote cell growth, proliferation, and survival. PIM kinases are commonly upregulated in both solid tumors and hematological malignancies. Recent studies [...] Read more.
The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases is a family of serine/threonine kinases that regulates numerous signaling networks that promote cell growth, proliferation, and survival. PIM kinases are commonly upregulated in both solid tumors and hematological malignancies. Recent studies have demonstrated that PIM facilitates immune evasion in cancer by promoting an immunosuppressive tumor microenvironment that suppresses the innate anti-tumor response. The role of PIM in immune evasion has sparked interest in examining the effect of PIM inhibition in combination with immunotherapy. This review focuses on the role of PIM kinases in regulating immune cell populations, how PIM modulates the immune tumor microenvironment to promote immune evasion, and how PIM inhibitors may be used to enhance the efficacy of immunotherapy. Full article
(This article belongs to the Special Issue Inhibiting Immune Checkpoint-Expressing Cells for Tumor Therapy)
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24 pages, 8109 KiB  
Review
Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3 Inhibitor
by Luisa Chocarro, Ana Bocanegra, Ester Blanco, Leticia Fernández-Rubio, Hugo Arasanz, Miriam Echaide, Maider Garnica, Pablo Ramos, Sergio Piñeiro-Hermida, Ruth Vera, David Escors and Grazyna Kochan
Cells 2022, 11(15), 2351; https://doi.org/10.3390/cells11152351 - 30 Jul 2022
Cited by 38 | Viewed by 6541
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role [...] Read more.
Immune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role as Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical trials which are demonstrating positive results, including promising bispecific molecules targeting LAG-3 simultaneously with other ICIs. Recently, a new dual anti-PD-1 (Nivolumab) and anti-LAG-3 (Relatimab) treatment developed by Bristol Myers Squibb (Opdualag), was approved by the Food and Drug Administration (FDA) as the first LAG-3 blocking antibody combination for unresectable or metastatic melanoma. This novel immunotherapy combination more than doubled median progression-free survival (PFS) when compared to nivolumab monotherapy (10.1 months versus 4.6 months). Here, we analyze the large clinical trial responsible for this historical approval (RELATIVITY-047), and discuss the preclinical and clinical developments that led to its jump into clinical practice. We will also summarize results achieved by other LAG-3 targeting molecules with promising anti-tumor activities currently under clinical development in phases I, I/II, II, and III. Opdualag will boost the entry of more LAG-3 targeting molecules into clinical practice, supporting the accumulating evidence highlighting the pivotal role of LAG-3 in cancer. Full article
(This article belongs to the Special Issue Inhibiting Immune Checkpoint-Expressing Cells for Tumor Therapy)
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17 pages, 850 KiB  
Review
Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes
by Yasmin Abaza and Amer M. Zeidan
Cells 2022, 11(14), 2249; https://doi.org/10.3390/cells11142249 - 20 Jul 2022
Cited by 33 | Viewed by 6696
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many solid tumors, with limited progress made in the area of myeloid malignancies. The low mutational burden of acute myeloid leukemia (AML) is one potential reason behind the lack of activity of T-cell harnessing [...] Read more.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many solid tumors, with limited progress made in the area of myeloid malignancies. The low mutational burden of acute myeloid leukemia (AML) is one potential reason behind the lack of activity of T-cell harnessing ICIs, particularly CTLA-4 and PD-1 inhibitors. Innate immune checkpoints play a critical role in the immune escape of AML and myelodysplastic syndromes (MDS). The CD47 targeting agent, magrolimab, has shown promising activity when combined with azacitidine in early phase trials conducted in AML and higher-risk MDS, especially among patients harboring a TP53 mutation. Similarly, sabatolimab (an anti-TIM-3 monoclonal antibody) plus hypomethylating agents have shown durable responses in higher-risk MDS and AML in early clinical trials. Randomized trials are currently ongoing to confirm the efficacy of these agents. In this review, we will present the current progress and future directions of immune checkpoint inhibition in AML and MDS. Full article
(This article belongs to the Special Issue Inhibiting Immune Checkpoint-Expressing Cells for Tumor Therapy)
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27 pages, 1095 KiB  
Review
Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: Progress, Challenges, and Prospects
by Shengjie Tang, Chao Qin, Haiyang Hu, Tao Liu, Yiwei He, Haiyang Guo, Hang Yan, Jun Zhang, Shoujun Tang and Haining Zhou
Cells 2022, 11(3), 320; https://doi.org/10.3390/cells11030320 - 19 Jan 2022
Cited by 73 | Viewed by 8756
Abstract
Non-small cell lung cancer is one of the most common types of malignances worldwide and the main cause of cancer-related deaths. Current treatment for NSCLC is based on surgical resection, chemotherapy, radiotherapy, and targeted therapy, with poor therapeutic effectiveness. In recent years, immune [...] Read more.
Non-small cell lung cancer is one of the most common types of malignances worldwide and the main cause of cancer-related deaths. Current treatment for NSCLC is based on surgical resection, chemotherapy, radiotherapy, and targeted therapy, with poor therapeutic effectiveness. In recent years, immune checkpoint inhibitors have applied in NSCLC treatment. A large number of experimental studies have shown that immune checkpoint inhibitors are safer and more effective than traditional therapeutic modalities and have allowed for the development of better guidance in the clinical treatment of advanced NSCLC patients. In this review, we describe clinical trials using ICI immunotherapies for NSCLC treatment, the available data on clinical efficacy, and the emerging evidence regarding biomarkers. Full article
(This article belongs to the Special Issue Inhibiting Immune Checkpoint-Expressing Cells for Tumor Therapy)
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23 pages, 759 KiB  
Review
Depleting Tumor Cells Expressing Immune Checkpoint Ligands—A New Approach to Combat Cancer
by Fabrizio Marcucci and Cristiano Rumio
Cells 2021, 10(4), 872; https://doi.org/10.3390/cells10040872 - 12 Apr 2021
Cited by 5 | Viewed by 2867
Abstract
Antibodies against inhibitory immune checkpoint molecules (ICPMs), referred to as immune checkpoint inhibitors (ICIs), have gained a prominent place in cancer therapy. Several ICIs in clinical use have been engineered to be devoid of effector functions because of the fear that ICIs with [...] Read more.
Antibodies against inhibitory immune checkpoint molecules (ICPMs), referred to as immune checkpoint inhibitors (ICIs), have gained a prominent place in cancer therapy. Several ICIs in clinical use have been engineered to be devoid of effector functions because of the fear that ICIs with preserved effector functions could deplete immune cells, thereby curtailing antitumor immune responses. ICPM ligands (ICPMLs), however, are often overexpressed on a sizeable fraction of tumor cells of many tumor types and these tumor cells display an aggressive phenotype with changes typical of tumor cells undergoing an epithelial-mesenchymal transition. Moreover, immune cells expressing ICPMLs are often endowed with immunosuppressive or immune-deviated functionalities. Taken together, these observations suggest that compounds with the potential of depleting cells expressing ICPMLs may become useful tools for tumor therapy. In this article, we summarize the current state of the art of these compounds, including avelumab, which is the only ICI targeting an ICPML with preserved effector functions that has gained approval so far. We also discuss approaches allowing to obtain compounds with enhanced tumor cell-depleting potential compared to native antibodies. Eventually, we propose treatment protocols that may be applied in order to optimize the therapeutic efficacy of compounds that deplete cells expressing ICPMLs. Full article
(This article belongs to the Special Issue Inhibiting Immune Checkpoint-Expressing Cells for Tumor Therapy)
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Other

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9 pages, 2643 KiB  
Systematic Review
Pathological Complete Response to Neoadjuvant Chemoimmunotherapy for Early Triple-Negative Breast Cancer: An Updated Meta-Analysis
by Alessandro Rizzo, Antonio Cusmai, Raffaella Massafra, Samantha Bove, Maria Colomba Comes, Annarita Fanizzi, Lucia Rinaldi, Silvana Acquafredda, Gennaro Gadaleta-Caldarola, Donato Oreste, Alfredo Zito, Francesco Giotta, Vito Lorusso and Gennaro Palmiotti
Cells 2022, 11(12), 1857; https://doi.org/10.3390/cells11121857 - 7 Jun 2022
Cited by 10 | Viewed by 3421
Abstract
Immune checkpoint inhibitors (ICIs) have made a breakthrough in the systemic treatment for metastatic triple-negative breast cancer (TNBC) patients. However, results of phase II and III clinical trials assessing ICIs plus chemotherapy as neoadjuvant treatment were controversial and conflicting. We performed a meta-analysis [...] Read more.
Immune checkpoint inhibitors (ICIs) have made a breakthrough in the systemic treatment for metastatic triple-negative breast cancer (TNBC) patients. However, results of phase II and III clinical trials assessing ICIs plus chemotherapy as neoadjuvant treatment were controversial and conflicting. We performed a meta-analysis aimed at assessing the Odds Ratio (OR) of the pathological complete response (pCR) rate in trials assessing neoadjuvant chemoimmunotherapy in TNBC. According to our results, the use of neoadjuvant chemoimmunotherapy was associated with higher pCR (OR 1.95; 95% Confidence Intervals, 1.27–2.99). In addition, we highlighted that this benefit was observed regardless of PD-L1 status since the analysis reported a statistically significant and clinically meaningful benefit in both PD-L1 positive and PD-L1 negative patients. These findings further support the exploration of the role of ICIs plus chemotherapy in early-stage TNBC, given the potentially meaningful clinical impact of these agents. Further studies aimed at more deeply investigating this emerging topic in breast cancer immunotherapy are warranted. Full article
(This article belongs to the Special Issue Inhibiting Immune Checkpoint-Expressing Cells for Tumor Therapy)
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