[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
You seem to have javascript disabled. Please note that many of the page functionalities won't work as expected without javascript enabled.
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
8.0
4.5
Journals
Cancers
Special Issues
Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators
share announcement

Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators

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

Deadline for manuscript submissions: 18 May 2025 | Viewed by 1943

Special Issue Editor

Dr. Katsuaki Ieguchi

E-Mail Website
Guest Editor
Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo, Japan
Interests: PD-1; PD-L1; CTLA-4; immune checkpoint molecule; immune checkpoint inhibitor; tumor microenvironment; biomarker; bispecific T-cell engager; bispecific DC-T cell engager

Special Issue Information

Dear Colleagues,

Immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibodies, disrupt interactions between immune checkpoint molecules and their ligands, thereby restoring T-cell-mediated cytotoxicity against tumor cells. ICIs are extensively employed in the treatment of various cancers, offering significant therapeutic benefits to patients. However, their efficacy is often limited, with some patients exhibiting resistance due to alternative immune evasion mechanisms. Additionally, current biomarkers for ICI-mediated therapy, including microsatellite instability and PD-L1 expression levels in tumors and lymphocytes, are insufficient for accurately predicting therapeutic outcomes. Therefore, addressing these limitations is crucial for enhancing the efficacy of ICIs in cancer treatment. 

Emerging approaches, such as bispecific T-cell engagers (BiTEs) and combination therapies involving cytotoxic agents and ICIs, such as antibody–drug conjugates (ADCs), have led to remarkable improvements in efficacy. In current clinical settings, these combination therapies have shown promising outcomes and may represent the most effective strategy for improving ICI efficacy. 

This Special Issue focuses on the molecular mechanisms underlying ICI treatment resistance, the identification and validation of biomarkers for predicting ICI efficacy, and strategies for improving ICI efficacy by modulating the tumor microenvironment. Additionally, discussions on preclinical tests involving small-molecule compounds, antibodies, and similar agents are welcome.

Dr. Katsuaki Ieguchi
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 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

  • PD-1
  • PD-L1
  • CTLA-4
  • immune checkpoint molecule
  • immune checkpoint inhibitor
  • tumor microenvironment
  • drug resistance
  • biomarker
  • BiTE
  • BiCE

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (1 paper)

Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

21 pages, 2769 KiB  
Article
IOS-1002, a Stabilized HLA-B57 Open Format, Exerts Potent Anti-Tumor Activity
by Anahita Rafiei, Marco Gualandi, Chia-Lung Yang, Richard Woods, Anil Kumar, Kathrin Brunner, John Sigrist, Hilmar Ebersbach, Steve Coats, Christoph Renner and Osiris Marroquin Belaunzaran
Cancers 2024, 16(16), 2902; https://doi.org/10.3390/cancers16162902 - 21 Aug 2024
Cited by 1 | Viewed by 1658
Abstract
HLA-B27 and HLA-B57 are associated with autoimmunity and long-term viral control and protection against HIV and HCV infection; however, their role in cancer immunity remains unknown. HLA class I molecules interact with innate checkpoint receptors of the LILRA, LILRB and KIR families present [...] Read more.
HLA-B27 and HLA-B57 are associated with autoimmunity and long-term viral control and protection against HIV and HCV infection; however, their role in cancer immunity remains unknown. HLA class I molecules interact with innate checkpoint receptors of the LILRA, LILRB and KIR families present in diverse sets of immune cells. Here, we demonstrate that an open format (peptide free conformation) and expression- and stability-optimized HLA-B57-B2m-IgG4_Fc fusion protein (IOS-1002) binds to human leukocyte immunoglobulin-like receptor B1 and B2 (LILRB1 and LILRB2) and to killer immunoglobulin-like receptor 3DL1 (KIR3DL1). In addition, we show that the IgG4 Fc backbone is required for engagement to Fcγ receptors and potent activation of macrophage phagocytosis. IOS-1002 blocks the immunosuppressive ITIM and SHP1/2 phosphatase signaling cascade, reduces the expression of immunosuppressive M2-like polarization markers of macrophages and differentiation of monocytes to myeloid-derived suppressor cells, enhances tumor cell phagocytosis in vitro and potentiates activation of T and NK cells. Lastly, IOS-1002 demonstrates efficacy in an ex vivo patient-derived tumor sample tumoroid model. IOS-1002 is a first-in-class multi-target and multi-functional human-derived HLA molecule that activates anti-tumor immunity and is currently under clinical evaluation. Full article
(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators)
►▼ Show Figures

Figure 1

Figure 1
<p>Structure, expression and receptor binding characteristics of IOS-1002. (<b>A</b>) Schematic representation of the IOS-1002 molecule constructed through the ligation of HLA-B57<sup>(A46E/V97R)</sup> on N-terminus of human IgG4 Fc domain. (<b>B</b>) The topological structure of HLA-B57:01:01 including the B2m molecule. Mutation site residues A46 and V97 highlighted as spheres (PDB: 5VUF). (<b>C</b>) SEC-HPLC profile of purified IOS-1002. (<b>D</b>) Thermal unfolding profile of IOS-1002, determined by DSF. (<b>E</b>) Quantification of the binding affinities of IOS-1002 to LILRB1 (<span class="html-italic">n</span> = 4), LILRB2 (<span class="html-italic">n</span> = 5) and KIR3DL1 (<span class="html-italic">n</span> = 1) surface receptors determined by SPR. Red line represents raw data and black line represents the fit of 1:1 binding. RU: response units; K<sub>D</sub>: binding constant represented as mean ± standard deviation. (<b>F</b>) The topological structure of the HLA-B57:01:01 interaction site generated by superimposing the HLA-B57 structure (PDB: 2HJK) onto LILRB1/HLA-G and LILRB2/HLA-G. The residues lining the binding interfaces between HLA-B57-B2m:LILRB1 and HLA-B57-B2m:LILRB2 are highlighted under the dashed circles and displayed as sticks. The crystal structure of HLA-B57:01 and KIR3DL1 allotype 015 (PDB: 5B39), which describes a separate epitope on the HLA-B57 α1-helix, incorporating residues 77–83, known as the Bw4 motif. Structural images generated using PyMOL. (<b>G</b>) Quantification of the binding affinity of IOS-1002 to FcγRI determined by SPR (<span class="html-italic">n</span> = 1). The specified <span class="html-italic">n</span> indicates the number of independent experiments.</p> Full article ">Figure 2
<p>IOS-1002 binds to target receptors on human primary cells and inhibits the associated downstream signaling. (<b>A</b>) CHO cells were transduced with LILRB1, LILRB2 and CD64 FcγRI and interaction of AF488 labeled molecules was measured by flow cytometry (<span class="html-italic">n</span> = 2). Mean ± standard deviation is presented. MFI: median of fluorescence intensity. (<b>B</b>) Dose-dependent binding of IOS-1002 on human primary monocytes and the monocyte-derived macrophages isolated from PBMCs (<span class="html-italic">n</span> = 4). Mean ± standard deviation is presented. MFI: mean of fluorescence intensity. The non-linear regression curve and EC<sub>50</sub> (95% Confidential Interval) were calculated using the model agonist vs. response variable slope (four parameters) in A and B. (<b>C</b>) Competition between IOS-1002, anti-LILRB1, anti-LILRB2, dual anti-LILRB1/2 and anti-CD64 antibody for cell surface epitopes on monocytes. Fold change of background-subtracted MFI relative to the cells pre-treated with IgG1 null antibody is presented, (<span class="html-italic">n</span> = 4). Mean ± standard deviation is presented. Statistical analysis of various conditions against IgG1 null control was performed using one-sample <span class="html-italic">t</span>-test (hypothetical mean = 1) and pre-treatment of combined dual anti-LILRB1/2 and anti-CD64 antibodies against anti-LILRB1/2 or anti-CD64 antibodies was analyzed by one-way ANOVA with Bonferroni multiple comparisons test. (<b>D</b>) Simple Western analysis showing expression and phosphorylation of ITIM-associated phosphatases, SHP-1 and SHP-2 in human primary monocytes-derived macrophages (<span class="html-italic">n</span> = 5). Quantification of phosphorylation over total protein relative to isotype control is presented in the graph on the right. Mean ± standard deviation is presented. Stars indicate the statistical significance against IgG4 control (one-sample <span class="html-italic">t</span>-test, hypothetical mean = 1). * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01; **** <span class="html-italic">p</span> &lt; 0.0001. ns, non-significant. In (<b>A</b>) <span class="html-italic">n</span> indicates the number of independent experiments, in (<b>B</b>–<b>D</b>) <span class="html-italic">n</span> indicates the number of independent donors.</p> Full article ">Figure 3
<p>IOS-1002 affects the differentiation of monocytes toward MDSCs and enhances phagocytosis of monocyte-derived macrophages. (<b>A</b>) Scheme of different monocyte-derived immune cell-based assays performed. (<b>B</b>,<b>C</b>) The effect of IOS-1002 on the differentiation potential of monocytes toward MDSCs (<span class="html-italic">n</span> = 3) (<b>B</b>) and M2 macrophages (<span class="html-italic">n</span> = 4) (<b>C</b>) is presented and compared with anti-LILRB2 antibody. Mean ± standard deviation is presented. In C, stars indicate the statistical significance toward IgG4 control. (<b>D</b>) Macrophage phagocytosis in the presence of different concentrations of IOS-1002 toward H460 (NSCLC cell line) (<span class="html-italic">n</span> = 4). Mean ± standard deviation of 3 technical replicates is presented. A 4P-L curve was interpolated for quantification of the EC<sub>50</sub>. (<b>E</b>) Macrophage phagocytosis in the presence of IOS-1002 on different Fc backbones toward H460 cell line (<span class="html-italic">n</span> = 2). Mean ± standard deviation is presented. Statistical analysis was performed using one-way ANOVA and Dunnett’s multiple comparisons test. Unless mentioned otherwise, all indicated compounds were used at a concentration of 20ug/mL. * <span class="html-italic">p</span>  &lt;  0.05, ** <span class="html-italic">p</span>  &lt;  0.01, *** <span class="html-italic">p</span>  &lt;  0.001. The specified <span class="html-italic">n</span> indicates the number of independent donors.</p> Full article ">Figure 4
<p>IOS-1002 activates T and NK cells and demonstrates efficacy in ex vivo patient samples. (<b>A</b>) Isolated human primary NK cells were incubated with HCT116 colon cancer cell line in a cell-cell contact manner and the percentage of cancer cell killing was measured for 60 h. Area under the curve (AUC) of the percent cytotoxicity over time was calculated and is represented in the graph (<span class="html-italic">n</span> = 4). Different colors represent independent donors. Statistical analysis was performed using RM one-way ANOVA with Dunnett’s multiple comparisons test. (<b>B</b>) Non-activated T cells were incubated with MIA PaCa-2 (pancreatic carcinoma, <span class="html-italic">n</span> = 2) and H1703 (NSCLC, <span class="html-italic">n</span> = 2) cancer cell lines in a cell-cell contact manner and co-cultures were monitored for 72 h; left, the T cells number at endpoint (72 h) is presented in fold changes over timepoint 0; right, the number of dead cancer cells at 72 h, expressed in percentage, is represented. Mean ± standard deviation is shown. Statistical analysis was performed using two-way ANOVA with Dunnet’s multiple comparisons. (<b>C</b>) TNFa levels in cell supernatant of PBMCs incubated with H1703 in a cell-cell contact manner for 48 h. TNFa concentration (pg/mL) for each individual donor is represented (<span class="html-italic">n</span> = 6). Every donor is color-coded throughout the treatments. Statistical analysis was performed using RM one-way ANOVA with Dunnett’s multiple comparisons test. Paired <span class="html-italic">t</span>-test analysis was used to compare activated PBMCs monoculture and PBS control co-culture. Act.: Activated, N. Act.: Non-activated. (<b>D</b>,<b>E</b>) Relative total tumoroid area normalized against the untreated sample and shown for individual patient samples (<b>D</b>) and in total cohort (<b>E</b>) upon different treatments. Each reported measurement is a median of up to 8 technical replicates. Imun15 sample has no SEA control recorded due to the technical error in the experiment. * <span class="html-italic">p</span>  &lt;  0.05, ** <span class="html-italic">p</span>  &lt;  0.01, *** <span class="html-italic">p</span>  &lt;  0.001. ns, non-significant. The specified <span class="html-italic">n</span> indicates the number of independent donors.</p> Full article ">
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-1
Back to TopTop