Small Molecules in Cancer Immunotherapy

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (25 June 2024) | Viewed by 2936

Special Issue Editors


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Guest Editor
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, FI, Italy
Interests: medicinal chemistry; rational drug design; heterocyclic compounds; structure–activity relationships; adenosine receptor ligands; carbonic anhydrase inhibitors; protein kinase CK1 and CK2 inhibitors; ecto-5'-nucleotidase (CD73) inhibitors
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, FI, Italy
Interests: medicinal chemistry; rational drug design; heterocyclic compounds; structure–activity relationships; adenosine receptor ligands; carbonic anhydrase inhibitors; protein kinase CK1 and CK2 inhibitors; ecto-5'-nucleotidase (CD73) inhibitors
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, FI, Italy
Interests: medicinal chemistry; rational drug design; heterocyclic compounds; structure–activity relationships; adenosine receptor ligands; carbonic anhydrase inhibitors; protein kinase CK1 and CK2 inhibitors; ecto-5'-nucleotidase (CD73) inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is a multifaceted disease and constitutes a great challenge to society, as it is the leading cause of mortality worldwide. There are different types of cancer that arise in different organs, each requiring specific pharmacological approaches. Cancer immunotherapy, either on its own or in combination with other strategies, represents the new frontier in oncological treatment. Immunotherapy enables the immune system to recognize and target cancer cells. Current cancer immunotherapies are mostly antibody-based, thereby possessing pharmacokinetic limitations such as long half-lives, poor tissue/tumor penetration, and scarce oral bioavailability. Furthermore, therapeutic antibodies may cause severe unwanted adverse effects due to their immunogenic nature. However, small molecules targeting defined pathways and/or cells involved in immunomodulation may overcome the abovementioned disadvantages, thus improving the efficacy of cancer therapy. Specifically, they act at the extracellular or intracellular levels, can be administrated orally, and their shorter half-lives could reduce the risk of systemic toxicity. Hence, the rapid development of small molecules for cancer immunotherapy has been witnessed over recent years.

Authors are invited to submit original articles presenting their research in this field. The proposed topic is in relation to small molecules as immunomodulators for cancer therapy, such as those targeting PD-1/PD-L1, chemokine receptors, Toll-like receptors, A2A/A2B adenosine receptors, and CD39/CD73. Moreover, review articles summarizing knowledge on these topics are also of interest.

Prof. Dr. Daniela Catarzi
Prof. Dr. Vittoria Colotta
Dr. Flavia Varano
Guest Editors

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Keywords

  • cancer immunotherapy
  • small molecules
  • immunocheckpoints
  • PD-1/PD-L1
  • A2A/A2B adenosine receptors
  • toll-like receptor
  • chemokine receptors
  • CD39/CD73

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Published Papers (2 papers)

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Research

13 pages, 4416 KiB  
Article
Cancer Cell Secreted Legumain Promotes Gastric Cancer Resistance to Anti-PD-1 Immunotherapy by Enhancing Macrophage M2 Polarization
by Xu Pei, Shi-Long Zhang, Bai-Quan Qiu, Peng-Fei Zhang, Tian-Shu Liu and Yan Wang
Pharmaceuticals 2024, 17(7), 951; https://doi.org/10.3390/ph17070951 - 16 Jul 2024
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Abstract
The interaction between cancer cells and immune cells plays critical roles in gastric cancer (GC) progression and immune evasion. Forced legumain (LGMN) is one of the characteristics correlated with poor prognosis in gastric cancer patients. However, the role of gastric-cancer-secreted LGMN (sLGMN) in [...] Read more.
The interaction between cancer cells and immune cells plays critical roles in gastric cancer (GC) progression and immune evasion. Forced legumain (LGMN) is one of the characteristics correlated with poor prognosis in gastric cancer patients. However, the role of gastric-cancer-secreted LGMN (sLGMN) in modulating the tumor immune microenvironment and the biological effect on the immune evasion of gastric cancer remains unclear. In this study, we found that forced expression of sLGMN in gastric cancer serum correlates with increased M2 macrophage infiltration in GC tissues and predicted resistance to anti-PD-1 immunotherapy. Mechanistically, gastric cancer cells secrete LGMN via binding to cell surface Integrin αvβ3, then activate Integrin αvβ3/PI3K (Phosphatidylinositol-4,5-bisphosphate3-kinase)/AKT (serine/threonine kinase)/mTORC2 (mammalian target of rapamycin complex 2) signaling, promote metabolic reprogramming, and polarize macrophages from the M1 to the M2 phenotype. Either blocking LGMN, Integrin αv, or knocking out Integrin αv expression and abolishing the LGMN/Integrin αvβ3 interaction significantly inhibits metabolic reprogramming and polarizes macrophages from the M1 to the M2 phenotype. This study reveals a critical molecular crosstalk between gastric cancer cells and macrophages through the sLGMN/Integrinαvβ3/PI3K/AKT/mTORC2 axis in promoting gastric cancer immune evasion and resistance to anti-PD-1 immunotherapy, indicating that the sLGMN/Integrinαvβ3/PI3K/AKT/mTORC2 axis may act as a promising therapeutic target. Full article
(This article belongs to the Special Issue Small Molecules in Cancer Immunotherapy)
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18 pages, 2513 KiB  
Article
Adenosine Increases the Immunosuppressive Capacity of Cervical Cancer Cells by Increasing PD-L1 Expression and TGF-β Production through Its Interaction with A2AR/A2BR
by Rosario García-Rocha, Alberto Monroy-García, Ana Luisa Vázquez-Cruz, Luis Antonio Marín-Aquino, Benny Weiss-Steider, Jorge Hernández-Montes, Christian Azucena Don-López, Gabriela Molina-Castillo and María de Lourdes Mora-García
Pharmaceuticals 2024, 17(3), 397; https://doi.org/10.3390/ph17030397 - 19 Mar 2024
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Abstract
The present study provides evidence showing that adenosine (Ado) increases the expression of programmed death ligand 1 (PD-L1) in cervical cancer (CeCa) cells by interacting with A2AR/A2BR and that TGF-β1 acts in an autocrine manner to induce PD-L1 expression, [...] Read more.
The present study provides evidence showing that adenosine (Ado) increases the expression of programmed death ligand 1 (PD-L1) in cervical cancer (CeCa) cells by interacting with A2AR/A2BR and that TGF-β1 acts in an autocrine manner to induce PD-L1 expression, enhancing the immunosuppressive effects of CeCa cells on activated T lymphocytes (ATLs) and CD8+ cytotoxic T lymphocytes (CTLs) specific for antigenic peptides derived from E6 and E7 proteins of HPV-16. Interestingly, the addition of the antagonists ZM241385 and MRS1754, which are specific for A2AR and A2BR, respectively, or SB-505124, which is a selective TGF-β1 receptor inhibitor, to CeCa cell cultures significantly inhibited PD-L1 expression. In addition, supernatants from CeCa cells that were treated with Ado (CeCa-Ado Sup) increased the expression of PD-1, TGF-β1, and IL-10 and decreased the expression of IFN-γ in ATLs. Interestingly, the addition of an anti-TGF-β neutralizing antibody strongly reversed the effect of CeCa-Ado Sup on PD-1 expression in ATLs. These results strongly suggest the presence of a feedback mechanism that involves the adenosinergic pathway, the production of TGF-β1, and the upregulation of PD-L1 expression in CeCa cells that suppresses the antitumor response of CTLs. The findings of this study suggest that this pathway may be clinically important and may be a therapeutic target. Full article
(This article belongs to the Special Issue Small Molecules in Cancer Immunotherapy)
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