Editorial

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Open AccessEditorial

Editorial on Special Issue “Immunotherapy, Tumor Microenvironment and Survival Signaling”

by Vita Golubovskaya

Cancers 2022, 14(1), 91; https://doi.org/10.3390/cancers14010091 - 24 Dec 2021

Viewed by 1862

Recently, novel types of immunotherapies such as CAR-T cell therapy demonstrated efficacy in leukemia, lymphoma, and multiple myeloma [...] Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

Research

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13 pages, 2539 KiB

Open AccessArticle

Novel CD37, Humanized CD37 and Bi-Specific Humanized CD37-CD19 CAR-T Cells Specifically Target Lymphoma

by Vita Golubovskaya, Hua Zhou, Feng Li, Michael Valentine, Jinying Sun, Robert Berahovich, Shirley Xu, Milton Quintanilla, Man Cheong Ma, John Sienkiewicz, Yanwei Huang and Lijun Wu

Cancers 2021, 13(5), 981; https://doi.org/10.3390/cancers13050981 - 26 Feb 2021

Cited by 13 | Viewed by 3649

Abstract

CD19 and CD37 proteins are highly expressed in B-cell lymphoma and have been successfully targeted with different monotherapies, including chimeric antigen receptor (CAR)-T cell therapy. The goal of this study was to target lymphoma with novel CD37, humanized CD37, and bi-specific humanized CD37-CD19 [...] Read more.

CD19 and CD37 proteins are highly expressed in B-cell lymphoma and have been successfully targeted with different monotherapies, including chimeric antigen receptor (CAR)-T cell therapy. The goal of this study was to target lymphoma with novel CD37, humanized CD37, and bi-specific humanized CD37-CD19 CAR-T cells. A novel mouse monoclonal anti-human CD37 antibody (clone 2B8D12F2D4) was generated with high binding affinity for CD37 antigen (KD = 1.6 nM). The CD37 antibody specifically recognized cell surface CD37 protein in lymphoma cells and not in multiple myeloma or other types of cancer. The mouse and humanized CD37-CAR-T cells specifically killed Raji and CHO-CD37 cells and secreted IFN-gamma. In addition, we generated bi-specific humanized hCD37-CD19 CAR-T cells that specifically killed Raji cells, CHO-CD37, and Hela-CD19 cells and did not kill control CHO or Hela cells. Moreover, the hCD37-CD19 CAR-T cells secreted IFN-gamma against CD37-positive and CD19-positive target CHO-CD37, Hela-CD19 cells, respectively, but not against CD19 and CD37-negative parental cell line. The bi-specific hCD37-CD19 significantly inhibited Raji xenograft tumor growth and prolonged mouse survival in NOD scid gamma mouse (NSG) mouse model. This study demonstrates that novel humanized CD37 and humanized CD37-CD19 CAR-T cells specifically targeted either CD37 positive or CD37 and CD19-positive cells and provides a basis for future clinical studies. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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17 pages, 4229 KiB

Open AccessArticle

DCLK1 Monoclonal Antibody-Based CAR-T Cells as a Novel Treatment Strategy against Human Colorectal Cancers

by Sripathi M. Sureban, Robert Berahovich, Hua Zhou, Shirley Xu, Lijun Wu, Kai Ding, Randal May, Dongfeng Qu, Edwin Bannerman-Menson, Vita Golubovskaya and Courtney W. Houchen

Cancers 2020, 12(1), 54; https://doi.org/10.3390/cancers12010054 - 23 Dec 2019

Cited by 36 | Viewed by 5077

Abstract

CAR-T (chimeric antigen receptor T cells) immunotherapy is effective in many hematological cancers; however, efficacy in solid tumors is disappointing. Doublecortin-like kinase 1 (DCLK1) labels tumor stem cells (TSCs) in genetic mouse models of colorectal cancer (CRC). Here, we describe a novel CAR-T [...] Read more.

CAR-T (chimeric antigen receptor T cells) immunotherapy is effective in many hematological cancers; however, efficacy in solid tumors is disappointing. Doublecortin-like kinase 1 (DCLK1) labels tumor stem cells (TSCs) in genetic mouse models of colorectal cancer (CRC). Here, we describe a novel CAR-T targeting DCLK1 (CBT-511; with our proprietary DCLK1 single-chain antibody variable fragment) as a treatment strategy to eradicate CRC TSCs. The cell surface expression of DCLK1 and cytotoxicity of CBT-511 were assessed in CRC cells (HT29, HCT116, and LoVo). LoVo-derived tumor xenografts in NOD Scid gamma (NSG™) mice were treated with CBT-511 or mock CAR-T cells. Adherent CRC cells express surface DCLK1 (two-dimensional, 2D). A 4.5-fold increase in surface DCLK1 was observed when HT29 cells were grown as spheroids (three-dimensional, 3D). CBT-511 induced cytotoxicity (2D; p < 0.0001), and increased Interferon gamma (IFN-γ) release in CRC cells (2D) compared to mock CAR-T (p < 0.0001). Moreover, an even greater increase in IFN-γ release was observed when cells were grown in 3D. CBT-511 reduced tumor growth by approximately 50 percent compared to mock CAR-T. These data suggest that CRC cells with increased clonogenic capacity express increased surface DCLK1. A DCLK1-targeted CAR-T can induce cytotoxicity in vitro and inhibit xenograft growth in vivo. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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19 pages, 5915 KiB

Open AccessArticle

Targeted Killing of Monocytes/Macrophages and Myeloid Leukemia Cells with Pro-Apoptotic Peptides

by Mouldy Sioud, Solveig Pettersen, Ieva Ailte and Yngvar Fløisand

Cancers 2019, 11(8), 1088; https://doi.org/10.3390/cancers11081088 - 31 Jul 2019

Cited by 11 | Viewed by 4713

Abstract

Several cells of myeloid origin, such as monocytes and macrophages are involved in various human disorders, including cancer and inflammatory diseases. Hence, they represent attractive therapeutic targets. Here we developed three lytic hybrid peptides, by fusing a monocyte- and macrophage-binding peptide to pro-apoptotic [...] Read more.

Several cells of myeloid origin, such as monocytes and macrophages are involved in various human disorders, including cancer and inflammatory diseases. Hence, they represent attractive therapeutic targets. Here we developed three lytic hybrid peptides, by fusing a monocyte- and macrophage-binding peptide to pro-apoptotic peptides, and investigated their killing potency on blood monocytes, macrophages, and leukemia cells. We first showed that the targeting NW peptide is effective for depleting monocytes from whole peripheral blood mononuclear cells (PBMCs). Incubating the cells with biotin-conjugated NW peptide, and the subsequent capture on streptavidin-conjugated magnetic beads, depleted monocytes from the PBMCs. The NW peptide also depleted myeloid leukemia blasts from patient PBMCs. The treatment of the PBMCs with the lytic hybrid NW-KLA peptide killed monocytes, but not lymphocytes and primary mammary epithelial cells. Additionally, the fusion peptide exhibited a potent toxicity against macrophages and leukemia cells. The free lytic KLA peptide did not affect cells. Similarly, a second lytic hybrid peptide killed macrophages, leukemia cell lines, and blood leukemia blasts from patients with acute and chronic myeloid leukemia. The IC₅₀ towards target cells were in the low macromolar range (4–12 µM). Overall, the data indicate that the NW peptide could be a potential drug delivery agent for monocytes, macrophages, and leukemia cells. Moreover, the engineered lytic hybrid peptides acting alone, or in combination with other therapeutic agents, might benefit many cancer patients and overcome drug resistance. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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13 pages, 1802 KiB

Open AccessArticle

Arming T Cells with a gp100-Specific TCR and a CSPG4-Specific CAR Using Combined DNA- and RNA-Based Receptor Transfer

by Bianca Simon, Dennis C. Harrer, Beatrice Schuler-Thurner, Gerold Schuler and Ugur Uslu

Cancers 2019, 11(5), 696; https://doi.org/10.3390/cancers11050696 - 20 May 2019

Cited by 22 | Viewed by 4158

Abstract

Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two [...] Read more.

Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two receptors into the same T cell to generate T cells expressing two additional receptors (TETARs). We generated these TETARs by lentiviral transduction of a gp100-specific T cell receptor (TCR) and subsequent electroporation of mRNA encoding a second-generation CSPG4-specific chimeric antigen receptor (CAR). Following pilot experiments to optimize the combined DNA- and RNA-based receptor transfer, the functionality of TETARs was compared to T cells either transfected with the TCR only or the CAR only. After transfection, TETARs clearly expressed both introduced receptors on their cell surface. When stimulated with tumor cells expressing either one of the antigens or both, TETARs were able to secrete cytokines and showed cytotoxicity. The confirmation that two antigen-specific receptors can be functionally combined using two different methods to introduce each receptor into the same T cell opens new possibilities and opportunities in cancer immunotherapy. For further evaluation, the use of these TETARs in appropriate animal models will be the next step towards a potential clinical use in cancer patients. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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16 pages, 24891 KiB

Open AccessArticle

Hypoxia Selectively Impairs CAR-T Cells In Vitro

by Robert Berahovich, Xianghong Liu, Hua Zhou, Elias Tsadik, Shirley Xu, Vita Golubovskaya and Lijun Wu

Cancers 2019, 11(5), 602; https://doi.org/10.3390/cancers11050602 - 30 Apr 2019

Cited by 53 | Viewed by 6926

Abstract

Hypoxia is a major characteristic of the solid tumor microenvironment. To understand how chimeric antigen receptor-T cells (CAR-T cells) function in hypoxic conditions, we characterized CD19-specific and BCMA-specific human CAR-T cells generated in atmospheric (18% oxygen) and hypoxic (1% oxygen) culture for expansion, [...] Read more.

Hypoxia is a major characteristic of the solid tumor microenvironment. To understand how chimeric antigen receptor-T cells (CAR-T cells) function in hypoxic conditions, we characterized CD19-specific and BCMA-specific human CAR-T cells generated in atmospheric (18% oxygen) and hypoxic (1% oxygen) culture for expansion, differentiation status, and CD4:CD8 ratio. CAR-T cells expanded to a much lower extent in 1% oxygen than in 18% oxygen. Hypoxic CAR-T cells also had a less differentiated phenotype and a higher CD4:CD8 ratio than atmospheric CAR-T cells. CAR-T cells were then added to antigen-positive and antigen-negative tumor cell lines at the same or lower oxygen level and characterized for cytotoxicity, cytokine and granzyme B secretion, and PD-1 upregulation. Atmospheric and hypoxic CAR-T cells exhibited comparable cytolytic activity and PD-1 upregulation; however, cytokine production and granzyme B release were greatly decreased in 1% oxygen, even when the CAR-T cells were generated in atmospheric culture. Together, these data show that at solid tumor oxygen levels, CAR-T cells are impaired in expansion, differentiation and cytokine production. These effects may contribute to the inability of CAR-T cells to eradicate solid tumors seen in many patients. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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17 pages, 3946 KiB

Open AccessArticle

Sequential Blockade of PD-1 and PD-L1 Causes Fulminant Cardiotoxicity—From Case Report to Mouse Model Validation

by Shin-Yi Liu, Wen-Chien Huang, Hung-I Yeh, Chun-Chuan Ko, Hui-Ru Shieh, Chung-Lieh Hung, Tung-Ying Chen and Yu-Jen Chen

Cancers 2019, 11(4), 580; https://doi.org/10.3390/cancers11040580 - 24 Apr 2019

Cited by 29 | Viewed by 5387

Abstract

The combined administration of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors might be considered as a treatment for poorly responsive cancer. We report a patient with brain metastatic lung adenocarcinoma in whom fatal myocarditis developed after sequential [...] Read more.

The combined administration of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors might be considered as a treatment for poorly responsive cancer. We report a patient with brain metastatic lung adenocarcinoma in whom fatal myocarditis developed after sequential use of PD-1 and PD-L1 inhibitors. This finding was validated in syngeneic tumor-bearing mice. The mice bearing lung metastases of CT26 colon cancer cells treated with PD-1 and/or PD-L1 inhibitors showed that the combination of anti-PD-1 and anti-PD-L1, either sequentially or simultaneously administered, caused myocarditis lesions with myocyte injury and patchy mononuclear infiltrates in the myocardium. A significant increase of infiltrating neutrophils in myocytes was noted only in mice with sequential blockade, implying a role for the pathogenesis of myocarditis. Among circulating leukocytes, concurrent and subsequent treatment of PD-1 and PD-L1 inhibitors led to sustained suppression of neutrophils. Among tumor-infiltrating leukocytes, combinatorial blockade increased CD8⁺ T cells and NKG2D⁺ T cells, and reduced tumor-associated macrophages, neutrophils, and natural killer (NK) cells in the lung metastatic microenvironment. The combinatorial treatments exhibited better control and anti-PD-L1 followed by anti-PD-1 was the most effective. In conclusion, the combinatory use of PD-1 and PD-L1 blockade, either sequentially or concurrently, may cause fulminant cardiotoxicity, although it gives better tumor control, and such usage should be cautionary. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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Review

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20 pages, 981 KiB

Open AccessReview

Damage-Associated Molecular Patterns Modulation by microRNA: Relevance on Immunogenic Cell Death and Cancer Treatment Outcome

by María Julia Lamberti, Annunziata Nigro, Vincenzo Casolaro, Natalia Belén Rumie Vittar and Jessica Dal Col

Cancers 2021, 13(11), 2566; https://doi.org/10.3390/cancers13112566 - 24 May 2021

Cited by 20 | Viewed by 2939

Abstract

Immunogenic cell death (ICD) in cancer is a functionally unique regulated form of stress-mediated cell death that activates both the innate and adaptive immune response against tumor cells. ICD makes dying cancer cells immunogenic by improving both antigenicity and adjuvanticity. The latter relies [...] Read more.

Immunogenic cell death (ICD) in cancer is a functionally unique regulated form of stress-mediated cell death that activates both the innate and adaptive immune response against tumor cells. ICD makes dying cancer cells immunogenic by improving both antigenicity and adjuvanticity. The latter relies on the spatiotemporally coordinated release or exposure of danger signals (DAMPs) that drive robust antigen-presenting cell activation. The expression of DAMPs is often constitutive in tumor cells, but it is the initiating stressor, called ICD-inducer, which finally triggers the intracellular response that determines the kinetics and intensity of their release. However, the contribution of cell-autonomous features, such as the epigenetic background, to the development of ICD has not been addressed in sufficient depth. In this context, it has been revealed that several microRNAs (miRNAs), besides acting as tumor promoters or suppressors, can control the ICD-associated exposure of some DAMPs and their basal expression in cancer. Here, we provide a general overview of the dysregulation of cancer-associated miRNAs whose targets are DAMPs, through which new molecular mediators that underlie the immunogenicity of ICD were identified. The current status of miRNA-targeted therapeutics combined with ICD inducers is discussed. A solid comprehension of these processes will provide a framework to evaluate miRNA targets for cancer immunotherapy. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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18 pages, 1609 KiB

Open AccessReview

Engineering Metabolism of Chimeric Antigen Receptor (CAR) Cells for Developing Efficient Immunotherapies

by Joslyn L. Mangal, Jamie L. Handlos, Arezoo Esrafili, Sahil Inamdar, Sidnee Mcmillian, Mamta Wankhede, Riccardo Gottardi and Abhinav P. Acharya

Cancers 2021, 13(5), 1123; https://doi.org/10.3390/cancers13051123 - 05 Mar 2021

Cited by 10 | Viewed by 4898

Abstract

Chimeric antigen receptor (CAR) T cell-based therapies have shown tremendous advancement in clinical and pre-clinical studies for the treatment of hematological malignancies, such as the refractory of pre-B cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), and large B cell lymphoma (LBCL). [...] Read more.

Chimeric antigen receptor (CAR) T cell-based therapies have shown tremendous advancement in clinical and pre-clinical studies for the treatment of hematological malignancies, such as the refractory of pre-B cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), and large B cell lymphoma (LBCL). However, CAR T cell therapy for solid tumors has not been successful clinically. Although, some research efforts, such as combining CARs with immune checkpoint inhibitor-based therapy, have been used to expand the application of CAR T cells for the treatment of solid tumors. Importantly, further understanding of the coordination of nutrient and energy supplies needed for CAR T cell expansion and function, especially in the tumor microenvironment (TME), is greatly needed. In addition to CAR T cells, there is great interest in utilizing other types of CAR immune cells, such as CAR NK and CAR macrophages that can infiltrate solid tumors. However, the metabolic competition in the TME between cancer cells and immune cells remains a challenge. Bioengineering technologies, such as metabolic engineering, can make a substantial contribution when developing CAR cells to have an ability to overcome nutrient-paucity in the solid TME. This review introduces technologies that have been used to generate metabolically fit CAR-immune cells as a treatment for hematological malignancies and solid tumors, and briefly discusses the challenges to treat solid tumors with CAR-immune cells. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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34 pages, 2411 KiB

Open AccessEditor’s ChoiceReview

The Functional Crosstalk between Myeloid-Derived Suppressor Cells and Regulatory T Cells within the Immunosuppressive Tumor Microenvironment

by Maximilian Haist, Henner Stege, Stephan Grabbe and Matthias Bros

Cancers 2021, 13(2), 210; https://doi.org/10.3390/cancers13020210 - 08 Jan 2021

Cited by 84 | Viewed by 9435

Abstract

Immune checkpoint inhibitors (ICI) have led to profound and durable tumor regression in some patients with metastatic cancer diseases. However, many patients still do not derive benefit from immunotherapy. Here, the accumulation of immunosuppressive cell populations within the tumor microenvironment (TME), such as [...] Read more.

Immune checkpoint inhibitors (ICI) have led to profound and durable tumor regression in some patients with metastatic cancer diseases. However, many patients still do not derive benefit from immunotherapy. Here, the accumulation of immunosuppressive cell populations within the tumor microenvironment (TME), such as myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and regulatory T cells (Treg), contributes to the development of immune resistance. MDSC and Treg expand systematically in tumor patients and inhibit T cell activation and T effector cell function. Numerous studies have shown that the immunosuppressive mechanisms exerted by those inhibitory cell populations comprise soluble immunomodulatory mediators and receptor interactions. The latter are also required for the crosstalk of MDSC and Treg, raising questions about the relevance of cell–cell contacts for the establishment of their inhibitory properties. This review aims to outline the current knowledge on the crosstalk between these two cell populations, issuing particularly the potential role of cell adhesion molecules. In this regard, we further discuss the relevance of β2 integrins, which are essential for the differentiation and function of leukocytes as well as for MDSC–Treg interaction. Lastly, we aim to describe the impact of such bidirectional crosstalk for basic and applied cancer research and discuss how the targeting of these pathways might pave the way for future approaches in immunotherapy. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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17 pages, 598 KiB

Open AccessReview

Tuft and Cancer Stem Cell Marker DCLK1: A New Target to Enhance Anti-Tumor Immunity in the Tumor Microenvironment

by Zhiyun Cao, Nathaniel Weygant, Parthasarathy Chandrakesan, Courtney W. Houchen, Jun Peng and Dongfeng Qu

Cancers 2020, 12(12), 3801; https://doi.org/10.3390/cancers12123801 - 17 Dec 2020

Cited by 27 | Viewed by 4619

Abstract

Microtubule-associated doublecortin-like kinase 1 (DCLK1) is an accepted marker of tuft cells (TCs) and several kinds of cancer stem cells (CSCs), and emerging evidence suggests that DCLK1-positive TCs participate in the initiation and formation of inflammation-associated cancer. DCLK1-expressing CSCs regulate multiple biological processes [...] Read more.

Microtubule-associated doublecortin-like kinase 1 (DCLK1) is an accepted marker of tuft cells (TCs) and several kinds of cancer stem cells (CSCs), and emerging evidence suggests that DCLK1-positive TCs participate in the initiation and formation of inflammation-associated cancer. DCLK1-expressing CSCs regulate multiple biological processes in cancer, promote resistance to therapy, and are associated with metastasis. In solid tumor cancers, tumor epithelia, immune cells, cancer-associated fibroblasts, endothelial cells and blood vessels, extracellular matrix, and hypoxia all support a CSC phenotype characterized by drug resistance, recurrence, and metastasis. Recently, studies have shown that DCLK1-positive CSCs are associated with epithelial-mesenchymal transition, angiogenesis, and immune checkpoint. Emerging data concerning targeting DCLK1 with small molecular inhibitors, monoclonal antibodies, and chimeric antigen receptor T-cells shows promising effects on inhibiting tumor growth and regulating the tumor immune microenvironment. Overall, DCLK1 is reaching maturity as an anti-cancer target and therapies directed against it may have potential against CSCs directly, in remodeling the tumor microenvironment, and as immunotherapies. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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24 pages, 49771 KiB

Open AccessReview

Cancer Immunotherapy and Application of Nanoparticles in Cancers Immunotherapy as the Delivery of Immunotherapeutic Agents and as the Immunomodulators

by Tilahun Ayane Debele, Cheng-Fa Yeh and Wen-Pin Su

Cancers 2020, 12(12), 3773; https://doi.org/10.3390/cancers12123773 - 15 Dec 2020

Cited by 30 | Viewed by 4116

Abstract

In the last few decades, cancer immunotherapy becomes an important tactic for cancer treatment. However, some immunotherapy shows certain limitations including poor therapeutic targeting and unwanted side effects that hinder its use in clinics. Recently, several researchers are exploring an alternative methodology to [...] Read more.

In the last few decades, cancer immunotherapy becomes an important tactic for cancer treatment. However, some immunotherapy shows certain limitations including poor therapeutic targeting and unwanted side effects that hinder its use in clinics. Recently, several researchers are exploring an alternative methodology to overcome the above limitations. One of the emerging tracks in this field area is nano-immunotherapy which has gone through rapid progress and revealed considerable potentials to solve limitations related to immunotherapy. Targeted and stimuli-sensitive biocompatible nanoparticles (NPs) can be synthesized to deliver immunotherapeutic agents in their native conformations to the site of interest to enhance their antitumor activity and to enhance the survival rate of cancer patients. In this review, we have discussed cancer immunotherapy and the application of NPs in cancer immunotherapy, as a carrier of immunotherapeutic agents and as a direct immunomodulator. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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34 pages, 2100 KiB

Open AccessFeature PaperReview

Current Progresses and Challenges of Immunotherapy in Triple-Negative Breast Cancer

by Karan Mediratta, Sara El-Sahli, Vanessa D’Costa and Lisheng Wang

Cancers 2020, 12(12), 3529; https://doi.org/10.3390/cancers12123529 - 26 Nov 2020

Cited by 60 | Viewed by 6954

Abstract

With improved understanding of the immunogenicity of triple-negative breast cancer (TNBC), immunotherapy has emerged as a promising candidate to treat this lethal disease owing to the lack of specific targets and effective treatments. While immune checkpoint inhibition (ICI) has been effectively used in [...] Read more.

With improved understanding of the immunogenicity of triple-negative breast cancer (TNBC), immunotherapy has emerged as a promising candidate to treat this lethal disease owing to the lack of specific targets and effective treatments. While immune checkpoint inhibition (ICI) has been effectively used in immunotherapy for several types of solid tumor, monotherapies targeting programmed death 1 (PD-1), its ligand PD-L1, or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have shown little efficacy for TNBC patients. Over the past few years, various therapeutic candidates have been reviewed, attempting to improve ICI efficacy on TNBC through combinatorial treatment. In this review, we describe the clinical limitations of ICI and illustrate candidates from an immunological, pharmacological, and metabolic perspective that may potentiate therapy to improve the outcomes of TNBC patients. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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12 pages, 2741 KiB

Open AccessReview

Intercellular Mitochondrial Transfer in the Tumor Microenvironment

by Hana Sahinbegovic, Tomas Jelinek, Matous Hrdinka, Juli R. Bago, Marcello Turi, Tereza Sevcikova, Amina Kurtovic-Kozaric, Roman Hajek and Michal Simicek

Cancers 2020, 12(7), 1787; https://doi.org/10.3390/cancers12071787 - 04 Jul 2020

Cited by 24 | Viewed by 6721

Abstract

Cell-to-cell communication is a fundamental process in every multicellular organism. In addition to membrane-bound and released factors, the sharing of cytosolic components represents a new, poorly explored signaling route. An extraordinary example of this communication channel is the direct transport of mitochondria between [...] Read more.

Cell-to-cell communication is a fundamental process in every multicellular organism. In addition to membrane-bound and released factors, the sharing of cytosolic components represents a new, poorly explored signaling route. An extraordinary example of this communication channel is the direct transport of mitochondria between cells. In this review, we discuss how intercellular mitochondrial transfer can be used by cancer cells to sustain their high metabolic requirements and promote drug resistance and describe relevant molecular players in the context of current and future cancer therapy. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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18 pages, 923 KiB

Open AccessReview

Immunotherapy in Pediatric Solid Tumors—A Systematic Review

by Raoud Marayati, Colin H. Quinn and Elizabeth A. Beierle

Cancers 2019, 11(12), 2022; https://doi.org/10.3390/cancers11122022 - 14 Dec 2019

Cited by 12 | Viewed by 4372

Abstract

Despite advances in the treatment of many pediatric solid tumors, children with aggressive and high-risk disease continue to have a dismal prognosis. For those presenting with metastatic or recurrent disease, multiple rounds of intensified chemotherapy and radiation are the typical course of action, [...] Read more.

Despite advances in the treatment of many pediatric solid tumors, children with aggressive and high-risk disease continue to have a dismal prognosis. For those presenting with metastatic or recurrent disease, multiple rounds of intensified chemotherapy and radiation are the typical course of action, but more often than not, this fails to control the progression of the disease. Thus, new therapeutics are desperately needed to improve the outcomes for these children. Recent advances in our understanding of both the immune system’s biology and its interaction with tumors have led to the development of novel immunotherapeutics as alternative treatment options for these aggressive malignancies. Immunotherapeutic approaches have shown promising results for pediatric solid tumors in early clinical trials, but challenges remain concerning safety and anti-tumor efficacy. In this review, we aim to discuss and summarize the main classes of immunotherapeutics used to treat pediatric solid tumors. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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18 pages, 1297 KiB

Open AccessReview

Immunotherapy: A Challenge of Breast Cancer Treatment

by Marilina García-Aranda and Maximino Redondo

Cancers 2019, 11(12), 1822; https://doi.org/10.3390/cancers11121822 - 20 Nov 2019

Cited by 108 | Viewed by 12812

Abstract

Breast cancer is the most commonly diagnosed cancer in women and is a leading cause of cancer death in women worldwide. Despite the significant benefit of the use of conventional chemotherapy and monoclonal antibodies in the prognosis of breast cancer patients and although [...] Read more.

Breast cancer is the most commonly diagnosed cancer in women and is a leading cause of cancer death in women worldwide. Despite the significant benefit of the use of conventional chemotherapy and monoclonal antibodies in the prognosis of breast cancer patients and although the recent approval of the anti-PD-L1 antibody atezolizumab in combination with chemotherapy has been a milestone for the treatment of patients with metastatic triple-negative breast cancer, immunologic treatment of breast tumors remains a great challenge. In this review, we summarize current breast cancer classification and standard of care, the main obstacles that hinder the success of immunotherapies in breast cancer patients, as well as different approaches that could be useful to enhance the response of breast tumors to immunotherapies. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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17 pages, 673 KiB

Open AccessReview

Immune Dysfunctions and Immunotherapy in Colorectal Cancer: The Role of Dendritic Cells

by Sandra Gessani and Filippo Belardelli

Cancers 2019, 11(10), 1491; https://doi.org/10.3390/cancers11101491 - 03 Oct 2019

Cited by 19 | Viewed by 3478

Abstract

Colorectal cancer (CRC), a multi-step malignancy showing increasing incidence in today’s societies, represents an important worldwide health issue. Exogenous factors, such as lifestyle, diet, nutrition, environment and microbiota, contribute to CRC pathogenesis, also influencing non neoplastic cells, including immune cells. Several immune dysfunctions [...] Read more.

Colorectal cancer (CRC), a multi-step malignancy showing increasing incidence in today’s societies, represents an important worldwide health issue. Exogenous factors, such as lifestyle, diet, nutrition, environment and microbiota, contribute to CRC pathogenesis, also influencing non neoplastic cells, including immune cells. Several immune dysfunctions were described in CRC patients at different disease stages. Many studies underline the role of microbiota, obesity-related inflammation, diet and host reactive cells, including dendritic cells (DC), in CRC pathogenesis. Here, we focused on DC, the main cells linking innate and adaptive anti-cancer immunity. Variations in the number and phenotype of circulating and tumor-infiltrating DC have been found in CRC patients and correlated with disease stages and progression. A critical review of DC-based clinical studies and of recent advances in cancer immunotherapy leads to consider new strategies for combining DC vaccination strategies with check-point inhibitors, thus opening perspectives for a more effective management of this neoplastic disease. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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19 pages, 2011 KiB

Open AccessReview

Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, Other Than Abscopal Effect: A Systematic Review

by Vito Longo, Oronzo Brunetti, Amalia Azzariti, Domenico Galetta, Patrizia Nardulli, Francesco Leonetti and Nicola Silvestris

Cancers 2019, 11(4), 539; https://doi.org/10.3390/cancers11040539 - 15 Apr 2019

Cited by 46 | Viewed by 7338

Abstract

Despite that the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a [...] Read more.

Despite that the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitourinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response such as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a higher expression of immune checkpoint molecules, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors in order to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve the response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitory receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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22 pages, 746 KiB

Open AccessReview

The Interplay of Autophagy and Tumor Microenvironment in Colorectal Cancer—Ways of Enhancing Immunotherapy Action

by Evangelos Koustas, Panagiotis Sarantis, Georgia Kyriakopoulou, Athanasios G. Papavassiliou and Michalis V. Karamouzis

Cancers 2019, 11(4), 533; https://doi.org/10.3390/cancers11040533 - 14 Apr 2019

Cited by 39 | Viewed by 5259

Abstract

Autophagy as a primary homeostatic and catabolic process is responsible for the degradation and recycling of proteins and cellular components. The mechanism of autophagy has a crucial role in several cellular functions and its dysregulation is associated with tumorigenesis, tumor–stroma interactions, and resistance [...] Read more.

Autophagy as a primary homeostatic and catabolic process is responsible for the degradation and recycling of proteins and cellular components. The mechanism of autophagy has a crucial role in several cellular functions and its dysregulation is associated with tumorigenesis, tumor–stroma interactions, and resistance to cancer therapy. A growing body of evidence suggests that autophagy is also a key regulator of the tumor microenvironment and cellular immune response in different types of cancer, including colorectal cancer (CRC). Furthermore, autophagy is responsible for initiating the immune response especially when it precedes cell death. However, the role of autophagy in CRC and the tumor microenvironment remains controversial. In this review, we identify the role of autophagy in tumor microenvironment regulation and the specific mechanism by which autophagy is implicated in immune responses during CRC tumorigenesis and the context of anticancer therapy. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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