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The Molecular Base of Tumor-Immune Interactions – Challenges and Promises to Beat Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 17898

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Dr. Peter J. K. Kuppen

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Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
Interests: colorectal cancer; tumor-immmune interactions; cancer genetics and epigenetics; immunotherapy; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The view on tumor development underwent a paradigm shift in the last 30 years: from ‘tumors are immune-ignored’ to ‘the immune system plays a central role in cancer’. This role is complex, and ranges from killing tumor cells to supporting tumor growth. The challenge is to further unravel the molecular interactions that are at the base of tumor-immune interactions. The promise is: this can be translated to new and effective therapies that will beat cancer.

Authors are invited to submit papers form preclinical work on tumor-immune interactions, including also new therapeutical approaches, with a focus on molecular aspects. Papers on clinical studies, with a clear experimental biomolecular background, are also very welcome.

Dr. Peter Kuppen
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

Tumor immunology
Immune response
Genetic profiling
Systems biology
Immune checkpoints
Immunoediting

Published Papers (6 papers)

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Research

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12 pages, 5442 KiB

Open AccessArticle

Macrophages CD163+ and Factor XIIIa+ Provide a First-Line Defence against Proliferative Verrucous Leukoplakia Antigens

by Mariana Paravani Palaçon, Camila de Oliveira Barbeiro, Darcy Fernandes, Mariel Ruivo Biancardi, Heitor Albergoni Silveira, Túlio Morandin Ferrisse, Jorge Esquiche León, Omar Kujan and Andreia Bufalino

Int. J. Mol. Sci. 2023, 24(6), 5242; https://doi.org/10.3390/ijms24065242 - 09 Mar 2023

Cited by 3 | Viewed by 1135

Abstract

This study aimed to evaluate the density of the dendritic cells (DCs) and macrophages in oral leukoplakia (OL) and proliferative verrucous leukoplakia (PVL) by immunohistochemical analysis. We analysed paraffined tissue samples of PVL (n = 27), OL (n = 20), and inflammatory fibrous hyperplasia (n = 20) as the control group using the immunomarkers for DCs (CD1a, CD207, CD83, CD208 and CD123) and macrophages (CD68, CD163, FXIIIa and CD209). A quantitative analysis of positive cells in the epithelial and subepithelial areas was determined. Our results showed a reduction in CD208+ cells in the subepithelial area of the OL and PVL compared to the control. Additionally, we found a higher density of FXIIIa+ and CD163+ cells in the subepithelial area in PVL compared to the OL and control. Four-way MANOVA revealed a relationship between increased CD123+ cell density in the subepithelial area of “high-risk” samples regardless of disease. Macrophages provide the first line of defence against PVL antigens, suggesting a distinct pattern of innate immune system activation in PVL compared to OL, which may contribute to the complexity and the high rate of malignant transformation in the PVL. Full article

(This article belongs to the Special Issue The Molecular Base of Tumor-Immune Interactions – Challenges and Promises to Beat Cancer)

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16 pages, 1822 KiB

Open AccessArticle

It Runs in the Bromodomain Family: Speckled Proteins (SP) Play a Role in the Antitumor Immune Response in Solid Tumors

by Monika Anna Rosochowicz, Julia Maria Lipowicz, Marianna Iga Karwacka, Julia Ostapowicz, Malgorzata Cisek, Andrzej Adam Mackiewicz and Patrycja Czerwinska

Int. J. Mol. Sci. 2023, 24(1), 549; https://doi.org/10.3390/ijms24010549 - 29 Dec 2022

Cited by 1 | Viewed by 1584

Abstract

Cells and immune cells in the extracellular matrix: Depending on the tumor type and variety of TAAs (tumor-associated antigens), immune infiltrates are composed of many different subpopulations of immune cells. Epigenetic changes are also considered to be characteristic of cancer. Epigenetic factors taking part in the regulation of gene expression include the VII group of bromodomain proteins (BrD)—SP-family proteins. Here, we used transcriptomic data from the TCGA database, as well as immunological evidence from ESTIMATE, TIP, and TIMER2.0 databases for various solid tumor types and harnessed several publicly available bioinformatic tools (such as GSEA and GSCA) to demonstrate mechanisms and interactions between BrD proteins and immune infiltrates in cancer. We present a consistently positive correlation between the SP-family genes and immune score regardless of the tumor type. The SP-family proteins correlate positively with T cells’ trafficking and infiltration into tumor. Our results also show an association between the high expression of SP family genes and enriched transcriptome profiles of inflammatory response and TNF-α signaling via NF-κβ. We also show that the SP-family proteins could be considered good predictors of high immune infiltration phenotypes. Full article

(This article belongs to the Special Issue The Molecular Base of Tumor-Immune Interactions – Challenges and Promises to Beat Cancer)

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28 pages, 5201 KiB

Open AccessArticle

Multi-Omics Immune Interaction Networks in Lung Cancer Tumorigenesis, Proliferation, and Survival

by Qing Ye, Justin Hickey, Kathleen Summers, Brianne Falatovich, Marieta Gencheva, Timothy D. Eubank, Alexey V. Ivanov and Nancy Lan Guo

Int. J. Mol. Sci. 2022, 23(23), 14978; https://doi.org/10.3390/ijms232314978 - 29 Nov 2022

Cited by 8 | Viewed by 2290

Abstract

There are currently no effective biomarkers for prognosis and optimal treatment selection to improve non-small cell lung cancer (NSCLC) survival outcomes. This study further validated a seven-gene panel for diagnosis and prognosis of NSCLC using RNA sequencing and proteomic profiles of patient tumors. Within the seven-gene panel, ZNF71 expression combined with dendritic cell activities defined NSCLC patient subgroups (n = 966) with distinct survival outcomes (p = 0.04, Kaplan–Meier analysis). ZNF71 expression was significantly associated with the activities of natural killer cells (p = 0.014) and natural killer T cells (p = 0.003) in NSCLC patient tumors (n = 1016) using Chi-squared tests. Overexpression of ZNF71 resulted in decreased expression of multiple components of the intracellular intrinsic and innate immune systems, including dsRNA and dsDNA sensors. Multi-omics networks of ZNF71 and the intracellular intrinsic and innate immune systems were computed as relevant to NSCLC tumorigenesis, proliferation, and survival using patient clinical information and in-vitro CRISPR-Cas9/RNAi screening data. From these networks, pan-sensitive and pan-resistant genes to 21 NCCN-recommended drugs for treating NSCLC were selected. Based on the gene associations with patient survival and in-vitro CRISPR-Cas9, RNAi, and drug screening data, MEK1/2 inhibitors PD-198306 and U-0126, VEGFR inhibitor ZM-306416, and IGF-1R inhibitor PQ-401 were discovered as potential targeted therapy that may also induce an immune response for treating NSCLC. Full article

(This article belongs to the Special Issue The Molecular Base of Tumor-Immune Interactions – Challenges and Promises to Beat Cancer)

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16 pages, 2136 KiB

Open AccessArticle

Correlation of Immunological and Histopathological Features with Gene Expression-Based Classifiers in Colon Cancer Patients

by Simone van de Weerd, Marloes A. Smit, Jessica Roelands, Wilma E. Mesker, Davide Bedognetti, Peter J. K. Kuppen, Hein Putter, Rob A. E. M. Tollenaar, Jeanine M. L. Roodhart, Wouter Hendrickx, Jan Paul Medema and J. Han J. M. van Krieken

Int. J. Mol. Sci. 2022, 23(20), 12707; https://doi.org/10.3390/ijms232012707 - 21 Oct 2022

Cited by 1 | Viewed by 1863

Abstract

The purpose of this study was to evaluate the association between four distinct histopathological features: (1) tumor infiltrating lymphocytes, (2) mucinous differentiation, (3) tumor-stroma ratio, plus (4) tumor budding and two gene expression-based classifiers—(1) consensus molecular subtypes (CMS) plus (2) colorectal cancer intrinsic subtypes (CRIS). All four histopathological features were retrospectively scored on hematoxylin and eosin sections of the most invasive part of the primary tumor in 218 stage II and III colon cancer patients from two independent cohorts (AMC-AJCC-90 and AC-ICAM). RNA-based CMS and CRIS assignments were independently obtained for all patients. Contingency tables were constructed and a χ2 test was used to test for statistical significance. Odds ratios with 95% confidence intervals were calculated. The presence of tumor infiltrating lymphocytes and a mucinous phenotype (>50% mucinous surface area) were strongly correlated with CMS1 (p < 0.001 and p = 0.008) and CRIS-A (p = 0.006 and p < 0.001). The presence of mucus (≥ 10%) was associated with CMS3: mucus was present in 64.1% of all CMS3 tumors (p < 0.001). Although a clear association between tumor-stroma ratio and CMS4 was established in this study (p = 0.006), still 32 out of 61 (52.5%) CMS4 tumors were scored as stroma-low, indicating that CMS4 tumors cannot be identified solely based on stromal content. Higher budding counts were seen in CMS4 and CRIS-B tumors (p = 0.045 and p = 0.046). No other associations of the measured parameters were seen for any of the other CRIS subtypes. Our analysis revealed clear associations between histopathologic features and CMS or CRIS subtypes. However, identification of distinct molecular subtypes solely based on histopathology proved to be infeasible. Combining both molecular and morphologic features could potentially improve patient stratification. Full article

(This article belongs to the Special Issue The Molecular Base of Tumor-Immune Interactions – Challenges and Promises to Beat Cancer)

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12 pages, 1646 KiB

Open AccessArticle

Glucose–Thymidine Ratio as a Metabolism Index Using ¹⁸F-FDG and ¹⁸F-FLT PET Uptake as a Potential Imaging Biomarker for Evaluating Immune Checkpoint Inhibitor Therapy

by Sera Oh, Hyewon Youn, Jin Chul Paeng, Young-Hwa Kim, Chul-Hee Lee, Hongyoon Choi, Keon Wook Kang, June-Key Chung and Gi Jeong Cheon

Int. J. Mol. Sci. 2022, 23(16), 9273; https://doi.org/10.3390/ijms23169273 - 17 Aug 2022

Cited by 1 | Viewed by 4511

Abstract

Immune checkpoint inhibitors (ICIs) are widely used in cancer immunotherapy, requiring effective methods for response monitoring. This study evaluated changes in ¹⁸F-2-fluoro-2-deoxy-D-glucose (FDG) and ¹⁸F-fluorothymidine (FLT) uptake by tumors following ICI treatment as potential imaging biomarkers in mice. Tumor uptakes of ¹⁸F-FDG and ¹⁸F-FLT were measured and compared between the ICI treatment and control groups. A combined imaging index of glucose–thymidine uptake ratio (GTR) was defined and compared between groups. In the ICI treatment group, tumor growth was effectively inhibited, and higher proportions of immune cells were observed. In the early phase, ¹⁸F-FDG uptake was higher in the treatment group, whereas ¹⁸F-FLT uptake was not different. There was no difference in ¹⁸F-FDG uptake between the two groups in the late phase. However, ¹⁸F-FLT uptake of the control group was markedly increased compared with the ICI treatment group. GTR was consistently higher in the ICI treatment group in the early and late phases. After ICI treatment, changes in tumor cell proliferation were observed with ¹⁸F-FLT, whereas ¹⁸F-FDG showed altered metabolism in both tumor and immune cells. A combination of ¹⁸F-FLT and ¹⁸F-FDG PET, such as GTR, is expected to serve as a potentially effective imaging biomarker for monitoring ICI treatment. Full article

(This article belongs to the Special Issue The Molecular Base of Tumor-Immune Interactions – Challenges and Promises to Beat Cancer)

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Review

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22 pages, 839 KiB

Open AccessReview

Triple-Negative Breast Cancer and Predictive Markers of Response to Neoadjuvant Chemotherapy: A Systematic Review

by Nadine S. van den Ende, Anh H. Nguyen, Agnes Jager, Marleen Kok, Reno Debets and Carolien H. M. van Deurzen

Int. J. Mol. Sci. 2023, 24(3), 2969; https://doi.org/10.3390/ijms24032969 - 03 Feb 2023

Cited by 17 | Viewed by 5333

Abstract

Around 40–50% of all triple-negative breast cancer (TNBC) patients achieve a pathological complete response (pCR) after treatment with neoadjuvant chemotherapy (NAC). The identification of biomarkers predicting the response to NAC could be helpful for personalized treatment. This systematic review provides an overview of putative biomarkers at baseline that are predictive for a pCR following NAC. Embase, Medline and Web of Science were searched for articles published between January 2010 and August 2022. The articles had to meet the following criteria: patients with primary invasive TNBC without distant metastases and patients must have received NAC. In total, 2045 articles were screened by two reviewers resulting in the inclusion of 92 articles. Overall, the most frequently reported biomarkers associated with a pCR were a high expression of Ki-67, an expression of PD-L1 and the abundance of tumor-infiltrating lymphocytes, particularly CD8+ T cells, and corresponding immune gene signatures. In addition, our review reveals proteomic, genomic and transcriptomic markers that relate to cancer cells, the tumor microenvironment and the peripheral blood, which also affect chemo-sensitivity. We conclude that a prediction model based on a combination of tumor and immune markers is likely to better stratify TNBC patients with respect to NAC response. Full article

(This article belongs to the Special Issue The Molecular Base of Tumor-Immune Interactions – Challenges and Promises to Beat Cancer)

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