Research

Jump to: Review

17 pages, 2150 KiB

Open AccessArticle

Development and Validation of Tumor Immunogenicity Based Gene Signature for Skin Cancer Risk Stratification

by Maryam Yavartanoo and Gwan-Su Yi

Int. J. Mol. Sci. 2021, 22(21), 12025; https://doi.org/10.3390/ijms222112025 - 06 Nov 2021

Cited by 3 | Viewed by 2405

Melanoma is one of the most aggressive types of skin cancer, with significant heterogeneity in overall survival. Currently, tumor-node-metastasis (TNM) staging is insufficient to provide accurate survival prediction and appropriate treatment decision making for several types of tumors, such as those in melanoma [...] Read more.

Melanoma is one of the most aggressive types of skin cancer, with significant heterogeneity in overall survival. Currently, tumor-node-metastasis (TNM) staging is insufficient to provide accurate survival prediction and appropriate treatment decision making for several types of tumors, such as those in melanoma patients. Therefore, the identification of more reliable prognosis biomarkers is urgently essential. Recent studies have shown that low immune cells infiltration is significantly associated with unfavorable clinical outcome in melanoma patients. Here we constructed a prognostic-related gene signature for melanoma risk stratification by quantifying the levels of several cancer hallmarks and identify the Wnt/β-catenin activation pathway as a primary risk factor for low tumor immunity. A series of bioinformatics and statistical methods were combined and applied to construct a Wnt-immune-related prognosis gene signature. With this gene signature, we computed risk scores for individual patients that can predict overall survival. To evaluate the robustness of the result, we validated the signature in multiple independent GEO datasets. Finally, an overall survival-related nomogram was established based on the gene signature and clinicopathological features. The Wnt-immune-related prognostic risk score could better predict overall survival compared with standard clinicopathological features. Our results provide a comprehensive map of the oncogene-immune-related gene signature that can serve as valuable biomarkers for better clinical decision making. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Figure 1

15 pages, 2676 KiB

Open AccessArticle

Repression of MUC1 Promotes Expansion and Suppressive Function of Myeloid-Derived Suppressor Cells in Pancreatic and Breast Cancer Murine Models

by Mahnaz Sahraei, Mukulika Bose, J. Alexa Sanders, Chandrav De, Lopamudra DasRoy, Sritama Nath, Cory R. Brouwer and Pinku Mukherjee

Int. J. Mol. Sci. 2021, 22(11), 5587; https://doi.org/10.3390/ijms22115587 - 25 May 2021

Cited by 10 | Viewed by 2920

Abstract

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC [...] Read more.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing syngeneic pancreatic (KCKO) or breast (C57MG) tumors. We observed enhanced tumor growth of pancreatic and breast tumors in the MUC1KO mice compared to the WT mice. Enhanced tumor growth in the MUC1KO mice was associated with increased numbers of suppressive MDSCs and T regulatory (Tregs) cells in the tumor microenvironment. Compared to the WT host, MUC1KO host showed higher levels of iNOS, ARG1, and TGF-β, thus promoting proliferation of MDSCs with an immature and immune suppressive phenotype. When co-cultured with effector T cells, MDSCs from MUC1KO mice led to higher repression of IL-2 and IFN-γ production by T cells as compared to MDSCs from WT mice. Lastly, MDSCs from MUC1KO mice showed higher levels of c-Myc and activated pSTAT3 as compared to MDSCs from WT mice, suggesting increased survival, proliferation, and prevention of maturation of MDSCs in the MUC1KO host. We report diminished T cell function in the KO versus WT mice. In summary, the data suggest that MUC1 may regulate signaling pathways that are critical to maintain the immunosuppressive properties of MDSCs. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Figure 1

14 pages, 6797 KiB

Open AccessArticle

Deep Learning in Pancreatic Tissue: Identification of Anatomical Structures, Pancreatic Intraepithelial Neoplasia, and Ductal Adenocarcinoma

by Mark Kriegsmann, Katharina Kriegsmann, Georg Steinbuss, Christiane Zgorzelski, Anne Kraft and Matthias M. Gaida

Int. J. Mol. Sci. 2021, 22(10), 5385; https://doi.org/10.3390/ijms22105385 - 20 May 2021

Cited by 18 | Viewed by 2926

Abstract

Identification of pancreatic ductal adenocarcinoma (PDAC) and precursor lesions in histological tissue slides can be challenging and elaborate, especially due to tumor heterogeneity. Thus, supportive tools for the identification of anatomical and pathological tissue structures are desired. Deep learning methods recently emerged, which [...] Read more.

Identification of pancreatic ductal adenocarcinoma (PDAC) and precursor lesions in histological tissue slides can be challenging and elaborate, especially due to tumor heterogeneity. Thus, supportive tools for the identification of anatomical and pathological tissue structures are desired. Deep learning methods recently emerged, which classify histological structures into image categories with high accuracy. However, to date, only a limited number of classes and patients have been included in histopathological studies. In this study, scanned histopathological tissue slides from tissue microarrays of PDAC patients (n = 201, image patches n = 81.165) were extracted and assigned to a training, validation, and test set. With these patches, we implemented a convolutional neuronal network, established quality control measures and a method to interpret the model, and implemented a workflow for whole tissue slides. An optimized EfficientNet algorithm achieved high accuracies that allowed automatically localizing and quantifying tissue categories including pancreatic intraepithelial neoplasia and PDAC in whole tissue slides. SmoothGrad heatmaps allowed explaining image classification results. This is the first study that utilizes deep learning for automatic identification of different anatomical tissue structures and diseases on histopathological images of pancreatic tissue specimens. The proposed approach is a valuable tool to support routine diagnostic review and pancreatic cancer research. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Figure 1

13 pages, 3019 KiB

Open AccessArticle

Prognostic Significance of Interferon-γ and Its Signaling Pathway in Early Breast Cancer Depends on the Molecular Subtypes

by Anne-Sophie Heimes, Franziska Härtner, Katrin Almstedt, Slavomir Krajnak, Antje Lebrecht, Marco J. Battista, Karolina Edlund, Walburgis Brenner, Annette Hasenburg, Ugur Sahin, Mathias Gehrmann, Jan G. Hengstler and Marcus Schmidt

Int. J. Mol. Sci. 2020, 21(19), 7178; https://doi.org/10.3390/ijms21197178 - 29 Sep 2020

Cited by 17 | Viewed by 2453

Abstract

Interferons are crucial for adaptive immunity and play an important role in the immune landscape of breast cancer. Using microarray-based gene expression analysis, we examined the subtype-specific prognostic significance of interferon-γ (IFN-γ) as a single gene as well as an IFN-γ signature covering [...] Read more.

Interferons are crucial for adaptive immunity and play an important role in the immune landscape of breast cancer. Using microarray-based gene expression analysis, we examined the subtype-specific prognostic significance of interferon-γ (IFN-γ) as a single gene as well as an IFN-γ signature covering the signaling pathway in 461 breast cancer patients. Prognostic significance of IFN-γ, as well as the IFN-γ signature for metastasis-free survival (MFS), were examined using Kaplan–Meier as well as univariate and multivariate Cox regression analyses in the whole cohort and in different molecular subtypes. The independent prognostic significance of IFN-γ as a single gene was limited to basal-like breast cancer (hazard ratio (HR) 2.779, 95% confidence interval (95% CI) 1.117–6.919, p = 0.028). In contrast, the IFN-γ-associated gene signature was an independent prognostic factor in the whole cohort (HR 2.287, 95% CI 1.410–3.633, p < 0.001) as well as in the basal-like (HR 3.458, 95% CI 1.154–10.359, p = 0.027) and luminal B (HR 2.690, 95% CI 1.416–5.112, p = 0.003) molecular subtypes. These results underline the subtype-dependent prognostic influence of the immune system in early breast cancer. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Figure 1

16 pages, 1916 KiB

Open AccessArticle

CD8 T Cell Score as a Prognostic Biomarker for Triple Negative Breast Cancer

by Masanori Oshi, Mariko Asaoka, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Takashi Ishikawa, Itaru Endo and Kazuaki Takabe

Int. J. Mol. Sci. 2020, 21(18), 6968; https://doi.org/10.3390/ijms21186968 - 22 Sep 2020

Cited by 116 | Viewed by 6535

Abstract

CD8 T cell is an essential component of tumor-infiltrating lymphocytes (TIL) and tumor immune microenvironment (TIME). Using the xCell CD8 T cell score of whole tumor gene expression data, we estimated these cells in total of 3837 breast cancer patients from TCGA, METABRIC [...] Read more.

CD8 T cell is an essential component of tumor-infiltrating lymphocytes (TIL) and tumor immune microenvironment (TIME). Using the xCell CD8 T cell score of whole tumor gene expression data, we estimated these cells in total of 3837 breast cancer patients from TCGA, METABRIC and various GEO cohorts. The CD8 score correlated strongly with expression of CD8 genes. The score was highest for triple-negative breast cancer (TNBC), and a high score was associated with high tumor immune cytolytic activity and better survival in TNBC but not other breast cancer subtypes. In TNBC, tumors with a high CD8 score had enriched expression of interferon (IFN)-α and IFN-γ response and allograft rejection gene sets, and greater infiltration of anti-cancerous immune cells. The score strongly correlated with CD4 memory T cells in TNBC, and tumors with both a high CD8 score and high CD4 memory T cell abundance had significantly better survival. Finally, a high CD8 score was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, a high CD8 T cell score is associated with better survival in TNBC, particularly when tumor CD4 memory T cells were elevated. Our findings also suggest a possible use of the score as a predictive biomarker for response to immune checkpoint therapy. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Figure 1

16 pages, 2967 KiB

Open AccessArticle

Identification of Gastritis Subtypes by Convolutional Neuronal Networks on Histological Images of Antrum and Corpus Biopsies

by Georg Steinbuss, Katharina Kriegsmann and Mark Kriegsmann

Int. J. Mol. Sci. 2020, 21(18), 6652; https://doi.org/10.3390/ijms21186652 - 11 Sep 2020

Cited by 17 | Viewed by 3064

Abstract

Background: Gastritis is a prevalent disease and commonly classified into autoimmune (A), bacterial (B), and chemical (C) type gastritis. While the former two subtypes are associated with an increased risk of developing gastric intestinal adenocarcinoma, the latter subtype is not. In this study, [...] Read more.

Background: Gastritis is a prevalent disease and commonly classified into autoimmune (A), bacterial (B), and chemical (C) type gastritis. While the former two subtypes are associated with an increased risk of developing gastric intestinal adenocarcinoma, the latter subtype is not. In this study, we evaluated the capability to classify common gastritis subtypes using convolutional neuronal networks on a small dataset of antrum and corpus biopsies. Methods: 1230 representative 500 × 500 µm images of 135 patients with type A, type B, and type C gastritis were extracted from scanned histological slides. Patients were allocated randomly into a training set (60%), a validation set (20%), and a test set (20%). One classifier for antrum and one classifier for corpus were trained and optimized. After optimization, the test set was analyzed using a joint result from both classifiers. Results: Overall accuracy in the test set was 84% and was particularly high for type B gastritis with a sensitivity of 100% and a specificity of 93%. Conclusions: Classification of gastritis subtypes is possible using convolutional neural networks on a small dataset of histopathological images of antrum and corpus biopsies. Deep learning strategies to support routine diagnostic pathology merit further evaluation. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Figure 1

16 pages, 3634 KiB

Open AccessArticle

Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15⁺ Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma

by Samantha M. Y. Chen, Bian Li, Andrew G. Nicklawsky, Alexandra L. Krinsky, Tonya Brunetti, Rachel A. Woolaver, Xiaoguang Wang, Zhangguo Chen, Christian D. Young, Dexiang Gao, Xiao-Jing Wang and Jing H. Wang

Int. J. Mol. Sci. 2020, 21(18), 6585; https://doi.org/10.3390/ijms21186585 - 09 Sep 2020

Cited by 7 | Viewed by 2664

Abstract

Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and loss-of-function [...] Read more.

Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and loss-of-function mutations of tumor protein p53 (TP53). However, it remains poorly understood whether HNSCCs harboring different genetic alterations exhibit differential immune tumor microenvironments (TME). It also remains unknown whether PIK3CA hyperactivation and TP53 deletion can lead to SCC development spontaneously. Here, we analyzed the Cancer Genome Atlas (TCGA) datasets of HNSCCs and found that patients with both PIK3CA and TP53 alterations exhibited worse survival, significantly lower CD8 tumor infiltrating lymphocytes (TILs) and higher M0 macrophages than other controls. To better model human tumorigenesis, we deleted TP53 and constitutively activated PIK3CA in mouse keratin-15-expressing stem cells, which leads to the spontaneous development of multilineage tumors including SCCs, termed Keratin-15-p53-PIK3CA (KPPA) tumors. KPPA tumors were heavily infiltrated with myeloid-derived suppressor cells (MDSCs), with a drastically increased ratio of polymorphonuclear-MDSC (PMN-MDSC) versus monocytic-MDSC (M-MDSC). CD8 TILs expressed more PD-1 and reduced their polyfunctionality. Overall, we established a genetic model to mimic human HNSCC pathogenesis, manifested with an immunosuppressive TME, which may help further elucidate immune evasion mechanisms and develop more effective immunotherapies for HNSCCs. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Figure 1

17 pages, 2281 KiB

Open AccessArticle

Contribution of Immune Cells to Glucocorticoid Receptor Expression in Breast Cancer

by Shipra Gandhi, Ahmed Elkhanany, Masanori Oshi, Tao Dai, Mateusz Opyrchal, Hemn Mohammadpour, Elizabeth A. Repasky and Kazuaki Takabe

Int. J. Mol. Sci. 2020, 21(13), 4635; https://doi.org/10.3390/ijms21134635 - 30 Jun 2020

Cited by 31 | Viewed by 4364

Abstract

Breast cancer (BC) patients experience increased stress with elevated cortisol levels, increasing risk of cancer recurrence. Cortisol binds to a cytoplasmic receptor, glucocorticoid receptor (GR) encoded by GR gene (NR3C1). We hypothesized that not only cancer cells, but even immune cells [...] Read more.

Breast cancer (BC) patients experience increased stress with elevated cortisol levels, increasing risk of cancer recurrence. Cortisol binds to a cytoplasmic receptor, glucocorticoid receptor (GR) encoded by GR gene (NR3C1). We hypothesized that not only cancer cells, but even immune cells in the tumor microenvironment (TME) may contribute to GR expression in bulk tumor and influence prognosis. To test this, mRNA expression data was accessed from METABRIC and TCGA. “High” and “low” expression was based on highest and lowest quartiles of NR3C1 gene expression, respectively. Single-cell sequencing data were obtained from GSE75688 and GSE114725 cohorts. Computer algorithms CIBERSORT, Gene Set Enrichment Analysis and TIMER were used. GR-high BC has better median disease-free and disease-specific survival. Single cell sequencing data showed higher GR expression on immune cells compared to cancer and stromal cells. Positive correlation between GR-high BC and CD8⁺ T-cells was noted. In GR-high tumors, higher cytolytic activity (CYT) with decreased T-regulatory and T-follicular helper cells was observed. High GR expression was associated with lower proliferation index Ki67, enriched in IL-2_STAT5, apoptosis, KRAS, TGF-β signaling, and epithelial-to-mesenchymal transition. Immune cells significantly contribute to GR expression of bulk BC. GR-high BC has a favorable TME with higher CYT with favorable outcomes. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Figure 1

18 pages, 4455 KiB

Open AccessArticle

Intratumoral Administration of a Novel Cytotoxic Formulation with Strong Tissue Dispersive Properties Regresses Tumor Growth and Elicits Systemic Adaptive Immunity in In Vivo Models

by Lewis H. Bender, Franco Abbate and Ian B. Walters

Int. J. Mol. Sci. 2020, 21(12), 4493; https://doi.org/10.3390/ijms21124493 - 24 Jun 2020

Cited by 7 | Viewed by 5284

Abstract

The recent development of immune-based therapies has improved the outcome for cancer patients; however, adjuvant therapies remain an important line of treatment for several cancer types. To maximize efficacy, checkpoint inhibitors are often combined with cytotoxic agents. While this approach often leads to [...] Read more.

The recent development of immune-based therapies has improved the outcome for cancer patients; however, adjuvant therapies remain an important line of treatment for several cancer types. To maximize efficacy, checkpoint inhibitors are often combined with cytotoxic agents. While this approach often leads to increased tumor regression, higher off target toxicity often results in certain patients. This report describes a novel formulation comprising a unique amphiphilic molecule, 8-((2-hydroxybenzoyl)amino)octanoate (SHAO), that non-covalently interacts with payloads to increase drug dispersion and diffusion when dosed intratumorally (IT) into solid tumors. SHAO is co-formulated with cisplatin and vinblastine (referred to as INT230-6). IT dosing of the novel formulation achieved greater tumor growth inhibition and improved survival in in vivo tumor models compared to the same drugs without enhancer given intravenously or IT. INT230-6 treatment increased immune infiltrating cells in injected tumors with 10% to 20% of the animals having complete responses and developing systemic immunity to the cancer. INT230-6 was also shown to be synergistic with programmed cell death protein 1 (PD-1) antibodies at improving survival and increasing complete responses. INT230-6 induced significant tumor necrosis potentially releasing antigens to induce the systemic immune-based anti-cancer attack. This research demonstrates a novel, local treatment approach for cancer that minimizes systemic toxicity while stimulating adaptive immunity. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Graphical abstract

19 pages, 2651 KiB

Open AccessArticle

Novel Autoantibody Signatures in Sera of Patients with Pancreatic Cancer, Chronic Pancreatitis and Autoimmune Pancreatitis: A Protein Microarray Profiling Approach

by Sahar Ghassem-Zadeh, Katrin Hufnagel, Andrea Bauer, Jean-Louis Frossard, Masaru Yoshida, Hiromu Kutsumi, Hans Acha-Orbea, Matthias Neulinger-Muñoz, Johannes Vey, Christoph Eckert, Oliver Strobel, Jörg D. Hoheisel and Klaus Felix

Int. J. Mol. Sci. 2020, 21(7), 2403; https://doi.org/10.3390/ijms21072403 - 31 Mar 2020

Cited by 11 | Viewed by 3017

Abstract

Identification of disease-associated autoantibodies is of high importance. Their assessment could complement current diagnostic modalities and assist the clinical management of patients. We aimed at developing and validating high-throughput protein microarrays able to screen patients’ sera to determine disease-specific autoantibody-signatures for pancreatic cancer [...] Read more.

Identification of disease-associated autoantibodies is of high importance. Their assessment could complement current diagnostic modalities and assist the clinical management of patients. We aimed at developing and validating high-throughput protein microarrays able to screen patients’ sera to determine disease-specific autoantibody-signatures for pancreatic cancer (PDAC), chronic pancreatitis (CP), autoimmune pancreatitis and their subtypes (AIP-1 and AIP-2). In-house manufactured microarrays were used for autoantibody-profiling of IgG-enriched preoperative sera from PDAC-, CP-, AIP-1-, AIP-2-, other gastrointestinal disease (GID) patients and healthy controls. As a top-down strategy, three different fluorescence detection-based protein-microarrays were used: large with 6400, intermediate with 345, and small with 36 full-length human recombinant proteins. Large-scale analysis revealed 89 PDAC, 98 CP and 104 AIP immunogenic antigens. Narrowing the selection to 29 autoantigens using pooled sera first and individual sera afterwards allowed a discrimination of CP and AIP from PDAC. For validation, predictive models based on the identified antigens were generated which enabled discrimination between PDAC and AIP-1 or AIP-2 yielded high AUC values of 0.940 and 0.925, respectively. A new repertoire of autoantigens was identified and their assembly as a multiplex test will provide a fast and cost-effective tool for differential diagnosis of pancreatic diseases with high clinical relevance. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Figure 1

Review

Jump to: Research

27 pages, 2674 KiB

Open AccessReview

Hijacked Immune Cells in the Tumor Microenvironment: Molecular Mechanisms of Immunosuppression and Cues to Improve T Cell-Based Immunotherapy of Solid Tumors

by Emre Balta, Guido H. Wabnitz and Yvonne Samstag

Int. J. Mol. Sci. 2021, 22(11), 5736; https://doi.org/10.3390/ijms22115736 - 27 May 2021

Cited by 28 | Viewed by 6500

Abstract

The understanding of the tumor microenvironment (TME) has been expanding in recent years in the context of interactions among different cell types, through direct cell–cell communication as well as through soluble factors. It has become evident that the development of a successful antitumor [...] Read more.

The understanding of the tumor microenvironment (TME) has been expanding in recent years in the context of interactions among different cell types, through direct cell–cell communication as well as through soluble factors. It has become evident that the development of a successful antitumor response depends on several TME factors. In this context, the number, type, and subsets of immune cells, as well as the functionality, memory, and exhaustion state of leukocytes are key factors of the TME. Both the presence and functionality of immune cells, in particular T cells, are regulated by cellular and soluble factors of the TME. In this regard, one fundamental reason for failure of antitumor responses is hijacked immune cells, which contribute to the immunosuppressive TME in multiple ways. Specifically, reactive oxygen species (ROS), metabolites, and anti-inflammatory cytokines have central roles in generating an immunosuppressive TME. In this review, we focused on recent developments in the immune cell constituents of the TME, and the micromilieu control of antitumor responses. Furthermore, we highlighted the current challenges of T cell-based immunotherapies and potential future strategies to consider for strengthening their effectiveness. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Graphical abstract

33 pages, 2819 KiB

Open AccessReview

The Immune Microenvironment in Pancreatic Cancer

by Magdalena Huber, Corinna U. Brehm, Thomas M. Gress, Malte Buchholz, Bilal Alashkar Alhamwe, Elke Pogge von Strandmann, Emily P. Slater, Jörg W. Bartsch, Christian Bauer and Matthias Lauth

Int. J. Mol. Sci. 2020, 21(19), 7307; https://doi.org/10.3390/ijms21197307 - 03 Oct 2020

Cited by 123 | Viewed by 8368

Abstract

The biology of solid tumors is strongly determined by the interactions of cancer cells with their surrounding microenvironment. In this regard, pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) represents a paradigmatic example for the multitude of possible tumor–stroma interactions. PDAC has proven particularly refractory [...] Read more.

The biology of solid tumors is strongly determined by the interactions of cancer cells with their surrounding microenvironment. In this regard, pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) represents a paradigmatic example for the multitude of possible tumor–stroma interactions. PDAC has proven particularly refractory to novel immunotherapies, which is a fact that is mediated by a unique assemblage of various immune cells creating a strongly immunosuppressive environment in which this cancer type thrives. In this review, we outline currently available knowledge on the cross-talk between tumor cells and the cellular immune microenvironment, highlighting the physiological and pathological cellular interactions, as well as the resulting therapeutic approaches derived thereof. Hopefully a better understanding of the complex tumor–stroma interactions will one day lead to a significant advancement in patient care. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Figure 1

20 pages, 2713 KiB

Open AccessReview

Hepatocellular Carcinoma—The Influence of Immunoanatomy and the Role of Immunotherapy

by Keyur Patel, Ryan Lamm, Peter Altshuler, Hien Dang and Ashesh P. Shah

Int. J. Mol. Sci. 2020, 21(18), 6757; https://doi.org/10.3390/ijms21186757 - 15 Sep 2020

Cited by 9 | Viewed by 4197

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality worldwide. Most patients are diagnosed with advanced disease, limiting their options for treatment. While current treatments are adequate for lower staged disease, available systemic treatments are limited, with marginal benefit at [...] Read more.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality worldwide. Most patients are diagnosed with advanced disease, limiting their options for treatment. While current treatments are adequate for lower staged disease, available systemic treatments are limited, with marginal benefit at best. Chimeric antigen receptor (CAR) T cell therapy, effective in treating liquid tumors such as B-cell lymphoma, presents a potentially promising treatment option for advanced HCC. However, new challenges specific to solid tumors, such as tumor immunoanatomy or the immune cell presence and position anatomically and the tumor microenvironment, need to be defined and overcome. Immunotherapy currently in use must be re-engineered and re-envisioned to treat HCC with the hopes of ushering in an answer to advanced stage solid tumor disease processes. Future therapy options must address the uniqueness of the tumors under the umbrella of HCC. This review strives to summarize HCC, its staging system, current therapy and immunotherapy medications currently being utilized or studied in the treatment of HCC with the hopes of highlighting what is being done and suggesting what needs to be done in the future to champion this therapy as an effective option. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Figure 1

22 pages, 861 KiB

Open AccessReview

The Latest Findings of PD-1/PD-L1 Inhibitor Application in Gynecologic Cancers

by Omid Kooshkaki, Afshin Derakhshani, Hossein Safarpour, Souzan Najafi, Parviz Vahedi, Oronzo Brunetti, Mitra Torabi, Parisa Lotfinejad, Angelo Virgilio Paradiso, Vito Racanelli, Nicola Silvestris and Behzad Baradaran

Int. J. Mol. Sci. 2020, 21(14), 5034; https://doi.org/10.3390/ijms21145034 - 16 Jul 2020

Cited by 29 | Viewed by 4514

Abstract

Gynecologic cancers account for approximately 11% of the newly diagnosed cancers in women in the United States and for 18% globally. The presence of tumor-infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICIs), including anti programmed cell [...] Read more.

Gynecologic cancers account for approximately 11% of the newly diagnosed cancers in women in the United States and for 18% globally. The presence of tumor-infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICIs), including anti programmed cell death protein-1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), and anticytotoxic T-lymphocyte antigen 4 (anti-CTLA-4), which have been approved for treating different types of malignancies. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host–tumor interaction. There are several the US food and drug administration (FDA)-approved ICIs targeting PD-1, including pembrolizumab and nivolumab, as well as those targeting PD-L1, including avelumab, atezolizumab, and durvalumab for melanoma, renal cell cancer, colorectal cancer, head and neck cancer, cervix cancer, urothelial cancer, and lung cancer. Current pre-clinical and clinical studies assessing PD-1/PD-L1 inhibitors in several gynecologic cancers have reported significant antitumor activity. In this review, we investigate pre-clinical and clinical studies that describe the safety and efficacy of anti-PD-1/PD-L1 antibodies, with a particular focus on ongoing clinical trials, analyzing the oncological outcome and adverse effects of ICIs in gynecologic cancers. Full article

(This article belongs to the Special Issue The Immune Landscape in Solid Tumors)

► Show Figures

Figure 1

Journal Menu

Journal Browser

The Immune Landscape in Solid Tumors

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (14 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI