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Open AccessEditorial

Immune Evasion as the Main Challenge for Immunotherapy of Cancer

by Radoslaw Zagozdzon, Magdalena Winiarska and Malgorzata Firczuk

Cancers 2022, 14(15), 3622; https://doi.org/10.3390/cancers14153622 - 26 Jul 2022

Cited by 5 | Viewed by 1876

Abstract

Immune evasion is currently considered one of the most prominent hallmarks of cancer [...] Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

Research

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21 pages, 4952 KiB

Open AccessArticle

PD-L1 Overexpression, SWI/SNF Complex Deregulation, and Profound Transcriptomic Changes Characterize Cancer-Dependent Exhaustion of Persistently Activated CD4⁺ T Cells

by Iga Jancewicz, Joanna Szarkowska, Ryszard Konopinski, Malgorzata Stachowiak, Monika Swiatek, Katarzyna Blachnio, Szymon Kubala, Paulina Oksinska, Pawel Cwiek, Natalia Rusetska, Agnieszka Tupalska, Natalia Zeber-Lubecka, Ewa Grabowska, Bianka Swiderska, Agata Malinowska, Michal Mikula, Beata Jagielska, Jan Walewski, Janusz A. Siedlecki, Tomasz J. Sarnowski, Sergiusz Markowicz and Elzbieta A. Sarnowska Show full author list Hide full author list

Cancers 2021, 13(16), 4148; https://doi.org/10.3390/cancers13164148 - 18 Aug 2021

Cited by 24 | Viewed by 5801

Abstract

Growing tumors avoid recognition and destruction by the immune system. During continuous stimulation of tumor-infiltrating lymphocytes (TILs) by tumors, TILs become functionally exhausted; thus, they become unable to kill tumor cells and to produce certain cytokines and lose their ability to proliferate. This [...] Read more.

Growing tumors avoid recognition and destruction by the immune system. During continuous stimulation of tumor-infiltrating lymphocytes (TILs) by tumors, TILs become functionally exhausted; thus, they become unable to kill tumor cells and to produce certain cytokines and lose their ability to proliferate. This collectively results in the immune escape of cancer cells. Here, we show that breast cancer cells expressing PD-L1 can accelerate exhaustion of persistently activated human effector CD4⁺ T cells, manifesting in high PD-1 and PD-L1 expression level son T cell surfaces, decreased glucose metabolism genes, strong downregulation of SWI/SNF chromatin remodeling complex subunits, and p21 cell cycle inhibitor upregulation. This results in inhibition of T cell proliferation and reduction of T cell numbers. The RNAseq analysis on exhausted CD4⁺ T cells indicated strong overexpression of IDO1 and genes encoding pro-inflammatory cytokines and chemokines. Some interleukins were also detected in media from CD4⁺ T cells co-cultured with cancer cells. The PD-L1 overexpression was also observed in CD4⁺ T cells after co-cultivation with other cell lines overexpressing PD-L1, which suggested the existence of a general mechanism of CD4⁺ T cell exhaustion induced by cancer cells. The ChIP analysis on the PD-L1 promoter region indicated that the BRM recruitment in control CD4⁺ T cells was replaced by BRG1 and EZH2 in CD4⁺ T cells strongly exhausted by cancer cells. These findings suggest that epi-drugs such as EZH2 inhibitors may be used as immunomodulators in cancer treatment. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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18 pages, 2682 KiB

Open AccessArticle

Hydrogen-Peroxide Synthesis and LDL-Uptake Controls Immunosuppressive Properties in Monocyte-Derived Dendritic Cells

by Ann-Katrin Menzner, Tanja Rottmar, Simon Voelkl, Jacobus J. Bosch, Dimitrios Mougiakakos, Andreas Mackensen and Yazid J. Resheq

Cancers 2021, 13(3), 461; https://doi.org/10.3390/cancers13030461 - 26 Jan 2021

Cited by 6 | Viewed by 3372

Abstract

Background and Aims: Induction of myeloid-derived suppressor cells (MDSC) is a critical step in immune cell evasion by different cancer types, including liver cancer. In the liver, hepatic stromal cells orchestrate induction of MDSCs, employing a mechanism dependent on hydrogen peroxide (H₂ [...] Read more.

Background and Aims: Induction of myeloid-derived suppressor cells (MDSC) is a critical step in immune cell evasion by different cancer types, including liver cancer. In the liver, hepatic stromal cells orchestrate induction of MDSCs, employing a mechanism dependent on hydrogen peroxide (H₂O₂) depletion. However, the effects on monocyte-derived dendritic cells (moDCs) are unknown. Methods: Monocytes from healthy donors were differentiated to moDCs in the presence of extracellular enzymatic H₂O₂-depletion (hereinafter CAT-DCs), and studied phenotypically and functionally. To elucidate the underlying molecular mechanisms, we analyzed H₂O₂- and LDL-metabolism as they are interconnected in monocyte-driven phagocytosis. Results: CAT-DCs were of an immature DC phenotype, particularly characterized by impaired expression of the costimulatory molecules CD80/86. Moreover, CAT-DCs were able to suppress T-cells using indoleamine 2,3-dioxygenase (IDO), and induced IL10/IL17-secreting T-cells—a subtype reported to exert immunosuppression in acute myeloid leukemia. CAT-DCs also displayed significantly increased NADPH-oxidase-driven H₂O₂-production, enhancing low-density lipoprotein (LDL)-uptake. Blocking LDL-uptake restored maturation, and attenuated the immunosuppressive properties of CAT-DCs. Discussion: Here, we report a novel axis between H₂O₂- and LDL-metabolism controlling tolerogenic properties in moDCs. Given that moDCs are pivotal in tumor-rejection, and lipid-accumulation is associated with tumor-immune-escape, LDL-metabolism appears to play an important role in tumor-immunology. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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Review

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17 pages, 2031 KiB

Open AccessReview

Perspectives for 3D-Bioprinting in Modeling of Tumor Immune Evasion

by Rafał Staros, Agata Michalak, Kinga Rusinek, Krzysztof Mucha, Zygmunt Pojda and Radosław Zagożdżon

Cancers 2022, 14(13), 3126; https://doi.org/10.3390/cancers14133126 - 26 Jun 2022

Cited by 13 | Viewed by 3390

Abstract

In a living organism, cancer cells function in a specific microenvironment, where they exchange numerous physical and biochemical cues with other cells and the surrounding extracellular matrix (ECM). Immune evasion is a clinically relevant phenomenon, in which cancer cells are able to direct [...] Read more.

In a living organism, cancer cells function in a specific microenvironment, where they exchange numerous physical and biochemical cues with other cells and the surrounding extracellular matrix (ECM). Immune evasion is a clinically relevant phenomenon, in which cancer cells are able to direct this interchange of signals against the immune effector cells and to generate an immunosuppressive environment favoring their own survival. A proper understanding of this phenomenon is substantial for generating more successful anticancer therapies. However, classical cell culture systems are unable to sufficiently recapture the dynamic nature and complexity of the tumor microenvironment (TME) to be of satisfactory use for comprehensive studies on mechanisms of tumor immune evasion. In turn, 3D-bioprinting is a rapidly evolving manufacture technique, in which it is possible to generate finely detailed structures comprised of multiple cell types and biomaterials serving as ECM-analogues. In this review, we focus on currently used 3D-bioprinting techniques, their applications in the TME research, and potential uses of 3D-bioprinting in modeling of tumor immune evasion and response to immunotherapies. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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32 pages, 1806 KiB

Open AccessReview

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

by Kuba Retecki, Milena Seweryn, Agnieszka Graczyk-Jarzynka and Malgorzata Bajor

Cancers 2021, 13(23), 6012; https://doi.org/10.3390/cancers13236012 - 29 Nov 2021

Cited by 29 | Viewed by 6167

Abstract

Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would [...] Read more.

Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would not bring benefits for breast cancer patients. Nevertheless, to date, a considerable number of reports have indicated tumor-infiltrating lymphocytes (TILs) as a prognostic and clinically relevant biomarker in breast cancer. A high TILs expression has been demonstrated in primary tumors, of both, HER2-positive BC and triple-negative (TNBC), of patients before treatment, as well as after treatment with adjuvant and neoadjuvant chemotherapy. Another milestone was reached in advanced TNBC immunotherapy with the help of the immune checkpoint inhibitors directed against the PD-L1 molecule. Although those findings, together with the recent developments in chimeric antigen receptor T cell therapies, show immense promise for significant advancements in breast cancer treatments, there are still various obstacles to the optimal activity of immunotherapeutics in BC treatment. Of these, the immunosuppressive tumor microenvironment constitutes a key barrier that greatly hinders the success of immunotherapies in the most aggressive types of breast cancer, HER2-positive and TNBC. Therefore, the improvement of the current and the demand for the development of new immunotherapeutic strategies is strongly warranted. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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27 pages, 1980 KiB

Open AccessReview

Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies

by Khiyam Hussain, Mark S. Cragg and Stephen A. Beers

Cancers 2021, 13(19), 4904; https://doi.org/10.3390/cancers13194904 - 29 Sep 2021

Cited by 8 | Viewed by 3806

Abstract

Among the diverse tumor resident immune cell types, tumor-associated macrophages (TAMs) are often the most abundant, possess an anti-inflammatory phenotype, orchestrate tumor immune evasion and are frequently associated with poor prognosis. However, TAMs can also be harnessed to destroy antibody-opsonized tumor cells through [...] Read more.

Among the diverse tumor resident immune cell types, tumor-associated macrophages (TAMs) are often the most abundant, possess an anti-inflammatory phenotype, orchestrate tumor immune evasion and are frequently associated with poor prognosis. However, TAMs can also be harnessed to destroy antibody-opsonized tumor cells through the process of antibody-dependent cellular phagocytosis (ADCP). Clinically important tumor-targeting monoclonal antibodies (mAb) such as Rituximab, Herceptin and Cetuximab, function, at least in part, by inducing macrophages to eliminate tumor cells via ADCP. For IgG mAb, this is mediated by antibody-binding activating Fc gamma receptors (FcγR), with resultant phagocytic activity impacted by the level of co-engagement with the single inhibitory FcγRIIb. Approaches to enhance ADCP in the tumor microenvironment include the repolarization of TAMs to proinflammatory phenotypes or the direct augmentation of ADCP by targeting so-called ‘phagocytosis checkpoints’. Here we review the most promising new strategies targeting the cell surface molecules present on TAMs, which include the inhibition of ‘don’t eat me signals’ or targeting immunostimulatory pathways with agonistic mAb and small molecules to augment tumor-targeting mAb immunotherapies and overcome therapeutic resistance. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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17 pages, 726 KiB

Open AccessReview

Neutrophil Extracellular Traps (NETs) in Cancer Invasion, Evasion and Metastasis

by Urszula Demkow

Cancers 2021, 13(17), 4495; https://doi.org/10.3390/cancers13174495 - 6 Sep 2021

Cited by 106 | Viewed by 9352

Abstract

The present review highlights the complex interactions between cancer and neutrophil extracellular traps (NETs). Neutrophils constitute the first line of defense against foreign invaders using major effector mechanisms: phagocytosis, degranulation, and NETs formation. NETs are composed from decondensed nuclear or mitochondrial DNA decorated [...] Read more.

The present review highlights the complex interactions between cancer and neutrophil extracellular traps (NETs). Neutrophils constitute the first line of defense against foreign invaders using major effector mechanisms: phagocytosis, degranulation, and NETs formation. NETs are composed from decondensed nuclear or mitochondrial DNA decorated with proteases and various inflammatory mediators. Although NETs play a crucial role in defense against systemic infections, they also participate in non-infectious conditions, such as inflammation, autoimmune disorders, and cancer. Cancer cells recruit neutrophils (tumor-associated neutrophils, TANs), releasing NETs to the tumor microenvironment. NETs were found in various samples of human and animal tumors, such as pancreatic, breast, liver, and gastric cancers and around metastatic tumors. The role of the NETs in tumor development increasingly includes cancer immunoediting and interactions between the immune system and cancer cells. According to the accumulated evidence, NETs awake dormant cancer cells, causing tumor relapse, as well as its unconstrained growth and spread. NETs play a key regulatory role in the tumor microenvironment, such as the development of distant metastases through the secretion of proteases, i.e., matrix metalloproteinases and proinflammatory cytokines. NETs, furthermore, directly exacerbate tumor aggressiveness by enhancing cancer migration and invasion capacity. The collected evidence also states that through the induction of the high-mobility group box 1, NETs induce the epithelial to mesenchymal transition in tumor cells and, thereby, potentiate their invasiveness. NET proteinases can also degrade the extracellular matrix, promoting cancer cell extravasation. Moreover, NETs can entrap circulating cancer cells and, in that way, facilitate metastasis. NETs directly trigger tumor cell proliferation through their proteases or activating signals. This review focused on the pro-tumorigenic action of NETs, in spite of its potential to also exhibit an antitumor effect. NET components, such as myeloperoxidase or histones, have been shown to directly kill cancer cells. A better understanding of the crosstalk between cancer and NETs can help to devise novel approaches to the therapeutic interventions that block cancer evasion mechanisms and prevent metastatic spread. This review sought to provide the most recent knowledge on the crosstalk between NETs and cancer, and bring more profound ideas for future scientists exploring this field. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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25 pages, 2340 KiB

Open AccessReview

The Role of Oncogenes and Redox Signaling in the Regulation of PD-L1 in Cancer

by Christophe Glorieux, Xiaojun Xia and Peng Huang

Cancers 2021, 13(17), 4426; https://doi.org/10.3390/cancers13174426 - 2 Sep 2021

Cited by 18 | Viewed by 3970

Abstract

Tumor cells can evade the immune system via multiple mechanisms, including the dysregulation of the immune checkpoint signaling. These signaling molecules are important factors that can either stimulate or inhibit tumor immune response. Under normal physiological conditions, the interaction between programmed cell death [...] Read more.

Tumor cells can evade the immune system via multiple mechanisms, including the dysregulation of the immune checkpoint signaling. These signaling molecules are important factors that can either stimulate or inhibit tumor immune response. Under normal physiological conditions, the interaction between programmed cell death ligand 1 (PD-L1) and its receptor, programmed cell death 1 (PD-1), negatively regulates T cell function. In cancer cells, high expression of PD-L1 plays a key role in cancer evasion of the immune surveillance and seems to be correlated with clinical response to immunotherapy. As such, it is important to understand various mechanisms by which PD-L1 is regulated. In this review article, we provide an up-to-date review of the different mechanisms that regulate PD-L1 expression in cancer. We will focus on the roles of oncogenic signals (c-Myc, EML4-ALK, K-ras and p53 mutants), growth factor receptors (EGFR and FGFR), and redox signaling in the regulation of PD-L1 expression and discuss their clinical relevance and therapeutic implications. These oncogenic signalings have common and distinct regulatory mechanisms and can also cooperatively control tumor PD-L1 expression. Finally, strategies to target PD-L1 expression in tumor microenvironment including combination therapies will be also discussed. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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22 pages, 1527 KiB

Open AccessReview

The Role of Macrophages in Cancer Development and Therapy

by Ewa Cendrowicz, Zuzanna Sas, Edwin Bremer and Tomasz P. Rygiel

Cancers 2021, 13(8), 1946; https://doi.org/10.3390/cancers13081946 - 18 Apr 2021

Cited by 168 | Viewed by 9574

Abstract

Macrophages are critical mediators of tissue homeostasis and influence various aspects of immunity. Tumor-associated macrophages are one of the main cellular components of the tumor microenvironment. Depending on their activation status, macrophages can exert a dual influence on tumorigenesis by either antagonizing the [...] Read more.

Macrophages are critical mediators of tissue homeostasis and influence various aspects of immunity. Tumor-associated macrophages are one of the main cellular components of the tumor microenvironment. Depending on their activation status, macrophages can exert a dual influence on tumorigenesis by either antagonizing the cytotoxic activity of immune cells or, less frequently, by enhancing antitumor responses. In most situations, TAMs suppress T cell recruitment and function or regulate other aspects of tumor immunity. The importance of TAMs targeting in cancer therapy is derived from the strong association between the high infiltration of TAMs in the tumor tissue with poor patient prognosis. Several macrophage-targeting approaches in anticancer therapy are developed, including TAM depletion, inhibition of new TAM differentiation, or re-education of TAM activation for cancer cell phagocytosis. In this review, we will describe the role of TAMs in tumor development, including such aspects as protumorigenic inflammation, immune suppression, neoangiogenesis, and enhancement of tissue invasion and distant metastasis. Furthermore, we will discuss therapeutic approaches that aim to deplete TAMs or, on the contrary, re-educate TAMs for cancer cell phagocytosis and antitumor immunity. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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25 pages, 742 KiB

Open AccessReview

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

by Agata Pastorczak, Krzysztof Domka, Klaudyna Fidyt, Martyna Poprzeczko and Malgorzata Firczuk

Cancers 2021, 13(7), 1536; https://doi.org/10.3390/cancers13071536 - 26 Mar 2021

Cited by 38 | Viewed by 6883

Abstract

Acute lymphoblastic leukemia (ALL) results from a clonal expansion of abnormal lymphoid progenitors of B cell (BCP-ALL) or T cell (T-ALL) origin that invade bone marrow, peripheral blood, and extramedullary sites. Leukemic cells, apart from their oncogene-driven ability to proliferate and avoid differentiation, [...] Read more.

Acute lymphoblastic leukemia (ALL) results from a clonal expansion of abnormal lymphoid progenitors of B cell (BCP-ALL) or T cell (T-ALL) origin that invade bone marrow, peripheral blood, and extramedullary sites. Leukemic cells, apart from their oncogene-driven ability to proliferate and avoid differentiation, also change the phenotype and function of innate and adaptive immune cells, leading to escape from the immune surveillance. In this review, we provide an overview of the genetic heterogeneity and treatment of BCP- and T-ALL. We outline the interactions of leukemic cells in the bone marrow microenvironment, mainly with mesenchymal stem cells and immune cells. We describe the mechanisms by which ALL cells escape from immune recognition and elimination by the immune system. We focus on the alterations in ALL cells, such as overexpression of ligands for various inhibitory receptors, including anti-phagocytic receptors on macrophages, NK cell inhibitory receptors, as well as T cell immune checkpoints. In addition, we describe how developing leukemia shapes the bone marrow microenvironment and alters the function of immune cells. Finally, we emphasize that an immunosuppressive microenvironment can reduce the efficacy of chemo- and immunotherapy and provide examples of preclinical studies showing strategies for improving ALL treatment by targeting these immunosuppressive interactions. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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29 pages, 2704 KiB

Open AccessReview

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

by Julian Swatler, Laura Turos-Korgul, Ewa Kozlowska and Katarzyna Piwocka

Cancers 2021, 13(6), 1203; https://doi.org/10.3390/cancers13061203 - 10 Mar 2021

Cited by 17 | Viewed by 4356

Abstract

Both chronic myeloid leukemia and acute myeloid leukemia evade the immune response during their development and disease progression. As myeloid leukemia cells modify their bone marrow microenvironment, they lead to dysfunction of cytotoxic cells, such as CD8+ T cells or NK cells, simultaneously [...] Read more.

Both chronic myeloid leukemia and acute myeloid leukemia evade the immune response during their development and disease progression. As myeloid leukemia cells modify their bone marrow microenvironment, they lead to dysfunction of cytotoxic cells, such as CD8+ T cells or NK cells, simultaneously promoting development of immunosuppressive regulatory T cells and suppressive myeloid cells. This facilitates disease progression, spreading of leukemic blasts outside the bone marrow niche and therapy resistance. The following review focuses on main immunosuppressive features of myeloid leukemias. Firstly, factors derived directly from leukemic cells – inhibitory receptors, soluble factors and extracellular vesicles, are described. Further, we outline function, properties and origin of main immunosuppressive cells - regulatory T cells, myeloid derived suppressor cells and macrophages. Finally, we analyze interplay between recovery of effector immunity and therapeutic modalities, such as tyrosine kinase inhibitors and chemotherapy. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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33 pages, 3962 KiB

Open AccessReview

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

by Tomasz M. Grzywa, Magdalena Justyniarska, Dominika Nowis and Jakub Golab

Cancers 2021, 13(4), 870; https://doi.org/10.3390/cancers13040870 - 19 Feb 2021

Cited by 30 | Viewed by 7150

Abstract

Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies [...] Read more.

Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce cancer-induced immunosuppression and the tumor-promoting effects of EPCs. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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20 pages, 1137 KiB

Open AccessReview

Immune Escape Mechanisms in Non Small Cell Lung Cancer

by Andrea Anichini, Valentina E. Perotti, Francesco Sgambelluri and Roberta Mortarini

Cancers 2020, 12(12), 3605; https://doi.org/10.3390/cancers12123605 - 2 Dec 2020

Cited by 110 | Viewed by 6003

Abstract

Development of strong immune evasion has been traditionally associated with the late stages of solid tumor progression, since advanced cancers are more likely to have reached the third phase of the immunoediting process. However, by integrating a variety of approaches, evidence for active [...] Read more.

Development of strong immune evasion has been traditionally associated with the late stages of solid tumor progression, since advanced cancers are more likely to have reached the third phase of the immunoediting process. However, by integrating a variety of approaches, evidence for active immune escape mechanisms has been found even in the pre-invasive lesions that later progress to the main NSCLC histotypes. Pre-invasive lesions of adenocarcinoma (LUAD) and of squamous cell carcinoma (LUSC) can show impaired antigen presentation, loss of heterozygosity at the Human Leukocyte Antigen (HLA) region, neoantigen silencing, activation of immune checkpoints, altered TH1/TH2 cytokine ratios, and immune contexture evolution. Analysis of large panels of LUAD vs. LUSC, of early stage NSCLC vs. normal lung tissue, of specific molecular subsets of NSCLC, and of distinct regions within the same tumor, indicates that all these processes of immune escape continue to evolve in the invasive stage of NSCLC, are associated with inter- and intra-tumor heterogeneity, and contribute to resistance to therapy by immune checkpoint blockade (ICB). In this review, we will discuss the most recent evidence on immune escape mechanisms developing from the precursor to invasive stage in NSCLC, and the contribution of immune evasion to resistance to ICB in lung cancer. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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36 pages, 1988 KiB

Open AccessReview

The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity

by Joanna Domagala, Mieszko Lachota, Marta Klopotowska, Agnieszka Graczyk-Jarzynka, Antoni Domagala, Andriy Zhylko, Karolina Soroczynska and Magdalena Winiarska

Cancers 2020, 12(12), 3542; https://doi.org/10.3390/cancers12123542 - 27 Nov 2020

Cited by 32 | Viewed by 5390

Abstract

NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with [...] Read more.

NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with malignant transformation and tumor progression lead to immunosuppression within the tumor microenvironment, which in turn limits the efficacy of various immunotherapies. In this review, we provide a brief description of the metabolic changes characteristic for the tumor microenvironment. Both tumor and tumor-associated cells produce and secrete factors that directly or indirectly prevent NK cell cytotoxicity. Here, we depict the molecular mechanisms responsible for the inhibition of immune effector cells by metabolic factors. Finally, we summarize the strategies to enhance NK cell function for the treatment of tumors. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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29 pages, 3587 KiB

Open AccessReview

The Great War of Today: Modifications of CAR-T Cells to Effectively Combat Malignancies

by Andriy Zhylko, Magdalena Winiarska and Agnieszka Graczyk-Jarzynka

Cancers 2020, 12(8), 2030; https://doi.org/10.3390/cancers12082030 - 24 Jul 2020

Cited by 18 | Viewed by 4126

Abstract

Immunotherapy of cancer had its early beginnings in the times when the elements of the immune system were still poorly characterized. However, with the progress in molecular biology, it has become feasible to re-engineer T cells in order to eradicate tumour cells. The [...] Read more.

Immunotherapy of cancer had its early beginnings in the times when the elements of the immune system were still poorly characterized. However, with the progress in molecular biology, it has become feasible to re-engineer T cells in order to eradicate tumour cells. The use of synthetic chimeric antigen receptors (CARs) helped to re-target and simultaneously unleash the cytotoxic potential of T cells. CAR-T therapy proved to be remarkably effective in cases of haematological malignancies, often refractory and relapsed. The success of this approach yielded two Food and Drug Administration (FDA) approvals for the first “living drug” modalities. However, CAR-T therapy is not without flaws. Apart from the side effects associated with the treatment, it became apparent that CAR introduction alters T cell biology and the possible therapeutic outcomes. Additionally, it was shown that CAR-T approaches in solid tumours do not recapitulate the success in the haemato-oncology. Therefore, in this review, we aim to discuss the recent concerns of CAR-T therapy for both haematological and solid tumours. We also summarise the general strategies that are implemented to enhance the efficacy and safety of the CAR-T regimens in blood and solid malignancies. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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14 pages, 1323 KiB

Open AccessReview

Gas6/Axl Signaling Pathway in the Tumor Immune Microenvironment

by Mai Tanaka and Dietmar W. Siemann

Cancers 2020, 12(7), 1850; https://doi.org/10.3390/cancers12071850 - 9 Jul 2020

Cited by 80 | Viewed by 14094

Abstract

Receptor tyrosine kinases have been shown to dysregulate a number of pathways associated with tumor development, progression, and metastasis. Axl is a receptor tyrosine kinase expressed in many cancer types and has been associated with therapy resistance and poor clinical prognosis and outcomes. [...] Read more.

Receptor tyrosine kinases have been shown to dysregulate a number of pathways associated with tumor development, progression, and metastasis. Axl is a receptor tyrosine kinase expressed in many cancer types and has been associated with therapy resistance and poor clinical prognosis and outcomes. In addition, Axl and its ligand growth arrest specific 6 (Gas6) protein are expressed by a number of host cells. The Gas6/Axl signaling pathway has been implicated in the promotion of tumor cell proliferation, survival, migration, invasion, angiogenesis, and immune evasion. As a result, Axl is an attractive, novel therapeutic target to impair multiple stages of tumor progression from both neoplastic and host cell axes. This review focuses on the role of the Gas6/Axl signaling pathway in promoting the immunosuppressive tumor microenvironment, as immune evasion is considered one of the hallmarks of cancer. The review discusses the structure and activation of the Gas6/Axl signaling pathway, GAS6 and AXL expression patterns in the tumor microenvironment, mechanisms of Axl-mediated tumor immune response, and the role of Gas6/Axl signaling in immune cell recruitment. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)

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