Special Issue "Targeting Innate Immunity Cells in Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 April 2020).

Special Issue Editor

Prof. Rafael Solana
Website
Guest Editor
Maimonides Biomedicine Institute of Cordoba (IMIBIC), Reina Sofia, University Hospital-University of Cordoba, Cordoba, Spain
Interests: immunosenescence; NK cells; T and NK cell-based immunotherapy; cytomegalovirus; leukemia

Special Issue Information

Dear Colleagues,

Advances in the better understanding of the relationship between the immune system and cancer have enabled the development of a broad arsenal of strategies aiming to target different aspects of the immune response for cancer treatment. Natural killer (NK) cells and other innate immunity cells are involved in the defense against tumors and viral infections. Their phenotype and function are strongly affected in patients with cancer. The deeper analysis of these cell alterations not only in cancer but also in other clinical conditions such as viral infection, chronic inflammation, autoimmunity, or ageing will contribute to the design of new therapeutic strategies aiming to modulate NK cell effector functions and to restore their antitumor functionality. In addition, therapeutic antibodies blocking checkpoints in innate immune cells, bispecific linker proteins, or NK cell-based adoptive cellular immunotherapy, including CAR-NK cells, can constitute new weapons to fight cancer. Thus, the aim of this Special Issue is to highlight recent studies on the interaction of NK and other innate immune cells with cancer cells and the potential to modulate innate immunity in cancer therapy.

Prof. Rafael Solana
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (21 papers)

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Research

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Open AccessArticle
Thioholgamide A, a New Anti-Proliferative Anti-Tumor Agent, Modulates Macrophage Polarization and Metabolism
Cancers 2020, 12(5), 1288; https://doi.org/10.3390/cancers12051288 - 19 May 2020
Abstract
Natural products represent powerful tools searching for novel anticancer drugs. Thioholgamide A (thioA) is a ribosomally synthesized and post-translationally modified peptide, which has been identified as a product of Streptomyces sp. MUSC 136T. In this study, we provide a comprehensive biological profile [...] Read more.
Natural products represent powerful tools searching for novel anticancer drugs. Thioholgamide A (thioA) is a ribosomally synthesized and post-translationally modified peptide, which has been identified as a product of Streptomyces sp. MUSC 136T. In this study, we provide a comprehensive biological profile of thioA, elucidating its effects on different hallmarks of cancer in tumor cells as well as in macrophages as crucial players of the tumor microenvironment. In 2D and 3D in vitro cell culture models thioA showed potent anti-proliferative activities in cancer cells at nanomolar concentrations. Anti-proliferative actions were confirmed in vivo in zebrafish embryos. Cytotoxicity was only induced at several-fold higher concentrations, as assessed by live-cell microscopy and biochemical analyses. ThioA exhibited a potent modulation of cell metabolism by inhibiting oxidative phosphorylation, as determined in a live-cell metabolic assay platform. The metabolic modulation caused a repolarization of in vitro differentiated and polarized tumor-promoting human monocyte-derived macrophages: ThioA-treated macrophages showed an altered morphology and a modulated expression of genes and surface markers. Taken together, the metabolic regulator thioA revealed low activities in non-tumorigenic cells and an interesting anti-cancer profile by orchestrating different hallmarks of cancer, both in tumor cells as well as in macrophages as part of the tumor microenvironment. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessArticle
Overexpression of Murine Rnaset2 in a Colon Syngeneic Mouse Carcinoma Model Leads to Rebalance of Intra-Tumor M1/M2 Macrophage Ratio, Activation of T Cells, Delayed Tumor Growth, and Rejection
Cancers 2020, 12(3), 717; https://doi.org/10.3390/cancers12030717 - 18 Mar 2020
Cited by 2
Abstract
Human RNASET2 acts as a powerful oncosuppressor protein in in vivo xenograft-based murine models of human cancer. Secretion of RNASET2 in the tumor microenvironment seems involved in tumor suppression, following recruitment of M1-polarized macrophages. Here, we report a murine Rnaset2-based syngeneic in [...] Read more.
Human RNASET2 acts as a powerful oncosuppressor protein in in vivo xenograft-based murine models of human cancer. Secretion of RNASET2 in the tumor microenvironment seems involved in tumor suppression, following recruitment of M1-polarized macrophages. Here, we report a murine Rnaset2-based syngeneic in vivo assay. BALB/c mice were injected with parental, empty vector-transfected or murine Rnaset2-overexpressing mouse C51 or TS/A syngeneic cells and tumor growth pattern and immune cells distribution in tumor mass were investigated. Compared to control cells, mouse Rnaset2-expressing C51 cells showed strong delayed tumor growth. CD86+ M1 macrophages were massively recruited in Rnaset2-expressing C51-derived tumors, with concomitant inhibition of MDSCs and CD206+ M2 macrophages recruitment. At later times, a relevant expansion of intra-tumor CD8+ T cells was also observed. After re-challenge with C51 parental cells, most mice previously injected with Rnaset2-expressing C51 cells still rejected C51 tumor cells, suggesting a Rnaset2-mediated T cell adaptive immune memory response. These results point at T2 RNases as evolutionary conserved oncosuppressors endowed with the ability to inhibit cancer growth in vivo through rebalance of intra-tumor M1/M2 macrophage ratio and concomitant recruitment of adaptive anti-tumor CD8+ T cells. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessArticle
Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor
Cancers 2020, 12(3), 661; https://doi.org/10.3390/cancers12030661 - 12 Mar 2020
Abstract
Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this [...] Read more.
Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this study, we have characterized the exosomes from IL2- or IL15-cultured human NK cells. Both cytokines induced comparable amounts of exosomes with similar cargo composition. Analysis of molecules contained within or exposed at the exosome surface, allowed the identification of molecules playing important roles in the NK cell function including IFN-γ, Lymphocyte Function-Associated Antigen (LFA-1), DNAX Accessory Molecule-1 (DNAM1) and Programmed Cell Death Protein (PD-1). Importantly, we show that DNAM1 is involved in exosome-mediated cytotoxicity as revealed by experiments using blocking antibodies to DNAM1 or DNAM1 ligands. In addition, antibody-mediated inhibition of exosome cytotoxicity results in a delay in target cell apoptosis. We also provide evidence that NK-exosomes may exert their cytolytic activity after short time interval and even at low concentrations. Regarding their possible use in immunotherapy, NK exosomes, detectable in peripheral blood, can diffuse into tissues and exert their cytolytic effect at tumor sites. This property offers a clue to integrate cancer treatments with NK exosomes. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessArticle
Differential Depletion of Bone Marrow Resident B-ALL after Systemic Administration of Endosomal TLR Agonists
Cancers 2020, 12(1), 169; https://doi.org/10.3390/cancers12010169 - 10 Jan 2020
Abstract
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. While frontline chemotherapy regimens are generally very effective, the prognosis for patients whose leukemia returns remains poor. The presence of measurable residual disease (MRD) in bone marrow at the completion of induction therapy [...] Read more.
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. While frontline chemotherapy regimens are generally very effective, the prognosis for patients whose leukemia returns remains poor. The presence of measurable residual disease (MRD) in bone marrow at the completion of induction therapy is the strongest predictor of relapse, suggesting that strategies to eliminate the residual leukemic blasts from this niche could reduce the incidence of recurrence. We have previously reported that toll-like receptor (TLR) agonists achieve durable T cell-mediated protection in transplantable cell line-based models of B cell precursor leukemia (B-ALL). However, the successful application of TLR agonist therapy in an MRD setting would require the induction of anti-leukemic immune activity specifically in the bone marrow, a site of the chemotherapy-resistant leukemic blasts. In this study, we compare the organ-specific depletion of human and mouse primary B-ALL cells after systemic administration of endosomal TLR agonists. Despite comparable splenic responses, only the TLR9 agonist induced strong innate immune responses in the bone marrow and achieved a near-complete elimination of B-ALL cells. This pattern of response was associated with the most significantly prolonged disease-free survival. Overall, our findings identify innate immune activity in the bone marrow that is associated with durable TLR-induced protection against B-ALL outgrowth. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessArticle
In the Absence of a TCR Signal IL-2/IL-12/18-Stimulated γδ T Cells Demonstrate Potent Anti-Tumoral Function Through Direct Killing and Senescence Induction in Cancer Cells
Cancers 2020, 12(1), 130; https://doi.org/10.3390/cancers12010130 - 04 Jan 2020
Abstract
Abundant IFN-γ secretion, potent cytotoxicity, and major histocompatibility complex-independent targeting of a large spectrum of tumors make γδ T cells attractive candidates for cancer immunotherapy. Upon tumor recognition through the T-cell receptor (TCR), NK-receptors, or NKG2D, γδ T cells generate the pro-inflammatory cytokines [...] Read more.
Abundant IFN-γ secretion, potent cytotoxicity, and major histocompatibility complex-independent targeting of a large spectrum of tumors make γδ T cells attractive candidates for cancer immunotherapy. Upon tumor recognition through the T-cell receptor (TCR), NK-receptors, or NKG2D, γδ T cells generate the pro-inflammatory cytokines TNF-α and IFN-γ, or granzymes and perforin that mediate cellular apoptosis. Despite these favorable potentials, most clinical trials testing the adoptive transfer of pharmacologically TCR-targeted and expanded γδ T cells resulted in a limited response. Recently, the TCR-independent activation of γδ T cells was identified. However, the modulation of γδ T cell’s effector functions solely by cytokines remains to be elucidated. In the present study, we systematically analyzed the impact of IL-2, IL-12, and IL-18 in parallel with TCR stimulation on proliferation, cytokine production, and anti-tumor activity of γδ T cells. Our results demonstrate that IL-12 and IL-18, when combined, constitute the most potent stimulus to enhance anti-tumor activity and induce proliferation and IFN-γ production by γδ T cells in the absence of TCR signaling. Intriguingly, stimulation with IL-12 and IL-18 without TCR stimulus induces a comparable degree of anti-tumor activity in γδ T cells to TCR crosslinking by killing tumor cells and driving cancer cells into senescence. These findings approve the use of IL-12/IL-18-stimulated γδ T cells for adoptive cell therapy to boost anti-tumor activity by γδ T cells. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessArticle
Induction of NK Cell Reactivity against B-Cell Acute Lymphoblastic Leukemia by an Fc-Optimized FLT3 Antibody
Cancers 2019, 11(12), 1966; https://doi.org/10.3390/cancers11121966 - 06 Dec 2019
Abstract
Antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism by which antitumor antibodies mediate therapeutic efficacy. At present, we evaluate an Fc-optimized (amino acid substitutions S239D/I332E) FLT3 antibody termed 4G8-SDIEM (FLYSYN) in patients with acute myeloid leukemia (NCT02789254). Here we studied the possibility to [...] Read more.
Antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism by which antitumor antibodies mediate therapeutic efficacy. At present, we evaluate an Fc-optimized (amino acid substitutions S239D/I332E) FLT3 antibody termed 4G8-SDIEM (FLYSYN) in patients with acute myeloid leukemia (NCT02789254). Here we studied the possibility to induce NK cell ADCC against B-cell acute lymphoblastic leukemia (B-ALL) by Fc-optimized FLT3 antibody treatment. Flow cytometric analysis confirmed that FLT3 is widely expressed on B-ALL cell lines and leukemic cells of B-ALL patients. FLT3 expression did not correlate with that of CD20, which is targeted by Rituximab, a therapeutic monoclonal antibody (mAb) employed in B-ALL treatment regimens. Our FLT3 mAb with enhanced affinity to the Fc receptor CD16a termed 4G8-SDIE potently induced NK cell reactivity against FLT3-transfectants, the B-ALL cell line SEM and primary leukemic cells of adult B-ALL patients in a target-antigen dependent manner as revealed by analyses of NK cell activation and degranulation. This was mirrored by potent 4G8-SDIE mediated NK cell ADCC in experiments with FLT3-transfectants, the cell line SEM and primary cells as target cells. Taken together, the findings presented in this study provide evidence that 4G8-SDIE may be a promising agent for the treatment of B-ALL, particularly in CD20-negative cases. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessArticle
IL-33 Promotes CD11b/CD18-Mediated Adhesion of Eosinophils to Cancer Cells and Synapse-Polarized Degranulation Leading to Tumor Cell Killing
Cancers 2019, 11(11), 1664; https://doi.org/10.3390/cancers11111664 - 26 Oct 2019
Cited by 3
Abstract
Eosinophils are major effectors of Th2-related pathologies, frequently found infiltrating several human cancers. We recently showed that eosinophils play an essential role in anti-tumor responses mediated by immunotherapy with the ‘alarmin’ intereukin-33 (IL-33) in melanoma mouse models. Here, we analyzed the mechanisms by [...] Read more.
Eosinophils are major effectors of Th2-related pathologies, frequently found infiltrating several human cancers. We recently showed that eosinophils play an essential role in anti-tumor responses mediated by immunotherapy with the ‘alarmin’ intereukin-33 (IL-33) in melanoma mouse models. Here, we analyzed the mechanisms by which IL-33 mediates tumor infiltration and antitumor activities of eosinophils. We show that IL-33 recruits eosinophils indirectly, via stimulation of tumor cell-derived chemokines, while it activates eosinophils directly, up-regulating CD69, the adhesion molecules ICAM-1 and CD11b/CD18, and the degranulation marker CD63. In co-culture experiments with four different tumor cell lines, IL-33-activated eosinophils established large numbers of stable cell conjugates with target tumor cells, with the polarization of eosinophil effector proteins (ECP, EPX, and granzyme-B) and CD11b/CD18 to immune synapses, resulting in efficient contact-dependent degranulation and tumor cell killing. In tumor-bearing mice, IL-33 induced substantial accumulation of degranulating eosinophils within tumor necrotic areas, indicating cytotoxic activity in vivo. Blocking of CD11b/CD18 signaling significantly reduced IL-33-activated eosinophils’ binding and subsequent killing of tumor cells, indicating a crucial role for this integrin in triggering degranulation. Our findings provide novel mechanistic insights for eosinophil-mediated anti-tumoral function driven by IL-33. Treatments enabling tumor infiltration and proper activation of eosinophils may improve therapeutic response in cancer patients. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessArticle
Extracellular Vesicles from Human Advanced-Stage Prostate Cancer Cells Modify the Inflammatory Response of Microenvironment-Residing Cells
Cancers 2019, 11(9), 1276; https://doi.org/10.3390/cancers11091276 - 30 Aug 2019
Abstract
Prostate cancer (PCa) progression is strictly associated with microenvironmental conditions, which can be modified by cancer-released extracellular vesicles (EVs), important mediators of cell-cell communication. However, the role of EVs in the inflammatory cross-talk between cancer cells and microenvironment-residing cells remains largely unknown. To [...] Read more.
Prostate cancer (PCa) progression is strictly associated with microenvironmental conditions, which can be modified by cancer-released extracellular vesicles (EVs), important mediators of cell-cell communication. However, the role of EVs in the inflammatory cross-talk between cancer cells and microenvironment-residing cells remains largely unknown. To evaluate the role of EVs in the tumour microenvironment, we treated the non-cancerous prostate cell line PNT2 with EVs isolated from advanced-stage prostate cancer PC3 (PC3-EVs). Caspase-1-mediated IL-1β maturation was evaluated after 24 h incubation with EVs. Moreover, the effect of PC3-EVs on differentiated macrophagic THP-1 cells was assessed by analyzing cytokine expression and PC3 cells migration and proliferation profiles. We illustrated that PC3 cells contain active NLRP3-inflammasome cascade and secrete IL-1β. PC3-EVs affect the PNT2 inflammatory response, inducing caspase-1-mediated IL-1β maturation via ERK1/2-mediated lysosomal destabilization and cathepsin B activation. We also verified that PC3-EVs induce a functional TAM-like polarization in differentiated THP-1 cells. Our results demonstrated that cancer-derived EVs induce an inflammatory response in non-cancerous prostate cells, while inducing an immunomodulatory phenotype in immune cells. These apparently contradictory effects are both committed to strengthening the tumour-promoting microenvironment Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessArticle
CD56 Homodimerization and Participation in Anti-Tumor Immune Effector Cell Functioning: A Role for Interleukin-15
Cancers 2019, 11(7), 1029; https://doi.org/10.3390/cancers11071029 - 22 Jul 2019
Abstract
A particularly interesting marker to identify anti-tumor immune cells is the neural cell adhesion molecule (NCAM), also known as cluster of differentiation (CD)56. Namely, hematopoietic expression of CD56 seems to be confined to powerful effector immune cells. Here, we sought to elucidate its [...] Read more.
A particularly interesting marker to identify anti-tumor immune cells is the neural cell adhesion molecule (NCAM), also known as cluster of differentiation (CD)56. Namely, hematopoietic expression of CD56 seems to be confined to powerful effector immune cells. Here, we sought to elucidate its role on various killer immune cells. First, we identified the high motility NCAM-120 molecule to be the main isoform expressed by immune cells. Next, through neutralization of surface CD56, we were able to (1) demonstrate the direct involvement of CD56 in tumor cell lysis exerted by CD56-expressing killer cells, such as natural killer cells, gamma delta (γδ) T cells, and interleukin (IL)-15-cultured dendritic cells (DCs), and (2) reveal a putative crosstalk mechanism between IL-15 DCs and CD8 T cells, suggesting CD56 as a co-stimulatory molecule in their cell-to-cell contact. Moreover, by means of a proximity ligation assay, we visualized the CD56 homophilic interaction among cancer cells and between immune cells and cancer cells. Finally, by blocking the mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase (PI3K)–Akt pathway, we showed that IL-15 stimulation directly led to CD56 upregulation. In conclusion, these results underscore the previously neglected importance of CD56 expression on immune cells, benefiting current and future immune therapeutic options. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessArticle
Cryopreserved Human Natural Killer Cells Exhibit Potent Antitumor Efficacy against Orthotopic Pancreatic Cancer through Efficient Tumor-Homing and Cytolytic Ability (Running Title: Cryopreserved NK Cells Exhibit Antitumor Effect)
Cancers 2019, 11(7), 966; https://doi.org/10.3390/cancers11070966 - 09 Jul 2019
Abstract
Pancreatic cancer is known to be highly aggressive, and desmoplasia-induced accumulation of extracellular matrix (ECM), which is a hallmark of many pancreatic cancers, severely restricts the therapeutic efficacy of both immunotherapeutics and conventional chemotherapeutics due to the ECM functioning as a major physical [...] Read more.
Pancreatic cancer is known to be highly aggressive, and desmoplasia-induced accumulation of extracellular matrix (ECM), which is a hallmark of many pancreatic cancers, severely restricts the therapeutic efficacy of both immunotherapeutics and conventional chemotherapeutics due to the ECM functioning as a major physical barrier against permeation and penetration. In the case of cell-based immunotherapeutics, there are several other bottlenecks preventing translation into clinical use due to their biological nature; for example, poor availability of cell therapeutic in a readily usable form due to difficulties in production, handling, shipping, and storage. To address these challenges, we have isolated allogeneic natural killer (NK) cells from healthy donors and expanded them in vitro to generate cryopreserved stocks. These cryopreserved NK cells were thawed to evaluate their therapeutic efficacy against desmoplastic pancreatic tumors, ultimately aiming to develop a readily accessible and mass-producible off-the-shelf cell-based immunotherapeutic. The cultured NK cells post-thawing retained highly pure populations of activated NK cells that expressed various activating receptors and a chemokine receptor. Furthermore, systemic administration of NK cells induced greater in vivo tumor growth suppression when compared with gemcitabine, which is the standard chemotherapeutic used for pancreatic cancer treatment. The potent antitumor effect of NK cells was mediated by efficient tumor-homing ability and infiltration into desmoplastic tumor tissues. Moreover, the infiltration of NK cells led to strong induction of apoptosis, elevated expression of the antitumor cytokine interferon (IFN)-γ, and inhibited expression of the immunosuppressive transforming growth factor (TGF)-β in tumor tissues. Expanded and cryopreserved NK cells are strong candidates for future cell-mediated systemic immunotherapy against pancreatic cancer. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessArticle
BCG Therapy of Bladder Cancer Stimulates a Prolonged Release of the Chemoattractant CXCL10 (IP10) in Patient Urine
Cancers 2019, 11(7), 940; https://doi.org/10.3390/cancers11070940 - 04 Jul 2019
Cited by 1
Abstract
Background: Intra-vesical instillation of Bacille Calmette–Guérin (BCG), an attenuated strain of Mycobacterium bovis, is an effective therapy for high-grade non-muscle invasive bladder cancer (NMIBC), which provokes a local immune response resulting in 70% of patients free of relapse after three years. Because [...] Read more.
Background: Intra-vesical instillation of Bacille Calmette–Guérin (BCG), an attenuated strain of Mycobacterium bovis, is an effective therapy for high-grade non-muscle invasive bladder cancer (NMIBC), which provokes a local immune response resulting in 70% of patients free of relapse after three years. Because non-responder patients usually have a bad prognosis, the early identification of treatment failure is crucial. We hypothesized that, if an effective immune response was taking place in the bladder, soluble factors would be released to the urine many days after BCG instillations. Methods: An extensive panel of cytokines and chemokines released into the urine seven days after every BCG instillation was screened in a cohort of NMIBC patients over three years. Results: The determinations of the urinary concentrations of cytokines, chemokines, and creatinine showed that increasing concentrations of C-X-C motif chemokine 10 (CXCL10) also known as interferon-inducible protein 10 (IP10) could be detected during the six-week induction cycle of BCG-treated patients released into the urine by CD14+ cells. In vitro, CXCL10 facilitated the recruitment of effector immune cells after the BCG-mediated upregulation of CXCR3 in both T- and natural killer (NK)-cells. Conclusions: The high concentrations of chemokine detected one week after the encounter with mycobacteria suggest that the CXCL10 axis might be related to the intensity of the immune anti-tumor response. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Review

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Open AccessFeature PaperReview
Targeting Mononuclear Phagocyte Receptors in Cancer Immunotherapy: New Perspectives of the Triggering Receptor Expressed on Myeloid Cells (TREM-1)
Cancers 2020, 12(5), 1337; https://doi.org/10.3390/cancers12051337 - 23 May 2020
Abstract
Inflammatory cells are major players in the onset of cancer. The degree of inflammation and type of inflammatory cells in the tumor microenvironment (TME) are responsible for tilting the balance between tumor progression and regression. Cancer-related inflammation has also been shown to influence [...] Read more.
Inflammatory cells are major players in the onset of cancer. The degree of inflammation and type of inflammatory cells in the tumor microenvironment (TME) are responsible for tilting the balance between tumor progression and regression. Cancer-related inflammation has also been shown to influence the efficacy of conventional therapy. Mononuclear phagocytes (MPs) represent a major component of the inflammatory circuit that promotes tumor progression. Despite their potential to activate immunosurveillance and exert anti-tumor responses, MPs are subverted by the tumor to support its growth, immune evasion, and spread. MP responses in the TME are dictated by a network of stimuli integrated through the cross-talk between activatory and inhibitory receptors. Alterations in receptor expression/signaling can create excessive inflammation and, when chronic, promote tumorigenesis. Research advances have led to the development of new therapeutic strategies aimed at receptor targeting to induce a tumor-infiltrating MP switch from a cancer-supportive toward an anti-tumor phenotype, demonstrating efficacy in different human cancers. This review provides an overview of the role of MP receptors in inflammation-mediated carcinogenesis and discusses the most recent updates regarding their targeting for immunotherapeutic purposes. We focus in particular on the TREM-1 receptor, a major amplifier of MP inflammatory responses, highlighting its relevance in the development and progression of several types of inflammation-associated malignancies and the promises of its inhibition for cancer immunotherapy. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessReview
Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches
Cancers 2020, 12(4), 926; https://doi.org/10.3390/cancers12040926 - 09 Apr 2020
Abstract
Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been [...] Read more.
Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri- and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessReview
Innate and Adaptive Immunity Linked to Recognition of Antigens Shared by Neural Crest-Derived Tumors
Cancers 2020, 12(4), 840; https://doi.org/10.3390/cancers12040840 - 31 Mar 2020
Abstract
In the adult, many embryologic processes can be co-opted by during cancer progression. The mechanisms of divisions, migration, and the ability to escape immunity recognition linked to specific embryo antigens are also expressed by malignant cells. In particular, cells derived from neural crests [...] Read more.
In the adult, many embryologic processes can be co-opted by during cancer progression. The mechanisms of divisions, migration, and the ability to escape immunity recognition linked to specific embryo antigens are also expressed by malignant cells. In particular, cells derived from neural crests (NC) contribute to the development of multiple cell types including melanocytes, craniofacial cartilage, glia, neurons, peripheral and enteric nervous systems, and the adrenal medulla. This plastic performance is due to an accurate program of gene expression orchestrated with cellular/extracellular signals finalized to regulate long-distance migration, proliferation, differentiation, apoptosis, and survival. During neurulation, prior to initiating their migration, NC cells must undergo an epithelial–mesenchymal transition (EMT) in which they alter their actin cytoskeleton, lose their cell–cell junctions, apicobasal polarity, and acquire a motile phenotype. Similarly, during the development of the tumors derived from neural crests, comprising a heterogeneous group of neoplasms (Neural crest-derived tumors (NCDTs)), a group of genes responsible for the EMT pathway is activated. Here, retracing the molecular pathways performed by pluripotent cells at the boundary between neural and non-neural ectoderm in relation to the natural history of NCDT, points of contact or interposition are highlighted to better explain the intricate interplay between cancer cells and the innate and adaptive immune response. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessReview
NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies
Cancers 2020, 12(4), 817; https://doi.org/10.3390/cancers12040817 - 28 Mar 2020
Abstract
Recent cancer treatment modalities have been intensively focused on immunotherapy. The success of chimeric antigen receptor T cell therapy for treatment of refractory B cell acute lymphoblastic leukemia has pushed forward research on hematological malignancies. Among the effector types of innate lymphocytes, natural [...] Read more.
Recent cancer treatment modalities have been intensively focused on immunotherapy. The success of chimeric antigen receptor T cell therapy for treatment of refractory B cell acute lymphoblastic leukemia has pushed forward research on hematological malignancies. Among the effector types of innate lymphocytes, natural killer (NK) cells show great importance in immune surveillance against infectious and tumor diseases. Particularly, the role of NK cells has been argued in either elimination of target tumor cells or escape of tumor cells from immune surveillance. Therefore, an NK cell activation approach has been explored. Recent findings demonstrate that invariant natural killer T (iNKT) cells capable of producing IFN-γ when optimally activated can promptly trigger NK cells. Here, we review the role of NKT and/or NK cells and their interaction in anti-tumor responses by highlighting how innate immune cells recognize tumors, exert effector functions, and amplify adaptive immune responses. In addition, we discuss these innate lymphocytes in hematological disorders, particularly multiple myeloma and acute myeloid leukemia. The immune balance at different stages of both diseases is explored in light of disease progression. Various types of innate immunity-mediated therapeutic approaches, recent advances in clinical immunotherapies, and iNKT-mediated cancer immunotherapy as next-generation immunotherapy are then discussed. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessReview
Targeted Therapies: Friends or Foes for Patient’s NK Cell-Mediated Tumor Immune-Surveillance?
Cancers 2020, 12(4), 774; https://doi.org/10.3390/cancers12040774 - 25 Mar 2020
Cited by 1
Abstract
In the last 20 years there has been a huge increase in the number of novel drugs for cancer treatment. Most of them exploit their ability to target specific oncogenic mutations in the tumors (targeted therapies–TT), while others target the immune-checkpoint inhibitor molecules [...] Read more.
In the last 20 years there has been a huge increase in the number of novel drugs for cancer treatment. Most of them exploit their ability to target specific oncogenic mutations in the tumors (targeted therapies–TT), while others target the immune-checkpoint inhibitor molecules (ICI) or the epigenetic DNA modifications. Among them, TT are the longest established drugs exploited against a wide spectrum of both solid and hematological tumors, often with reasonable costs and good efficacy as compared to other innovative therapies (i.e., ICI). Although they have greatly improved the treatment of cancer patients and their survival, patients often relapse or develop drug-resistance, leading to the impossibility to eradicate the disease. The outcome of TT has been often correlated with their ability to affect not only tumor cells, but also the repertoire of immune cells and their ability to interact with cancer cells. Thus, the possibility to create novel synergies among drugs an immunotherapy prompted scientists and physicians to deeply characterize the effects of TT on immune cells both by in-vitro and by ex-vivo analyses. In this context, NK cells may represent a key issue, since they have been shown to exert a potent anti-tumor activity, both against hematological malignancies and solid tumors. In the present review we will discuss most recent ex-vivo analyses that clarify the effect of TT treatment on patient’s NK cells comparing them with clinical outcome and previous in-vitro data. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessReview
Human Endogenous Retroviruses (HERVs): Shaping the Innate Immune Response in Cancers
Cancers 2020, 12(3), 610; https://doi.org/10.3390/cancers12030610 - 06 Mar 2020
Abstract
Human Endogenous Retroviruses (HERVs) are accounting for 8% of the human genome. These sequences are remnants from ancient germline infections by exogenous retroviruses. After million years of evolution and multiple integrations, HERVs have acquired many damages rendering them defective. At steady state, HERVs [...] Read more.
Human Endogenous Retroviruses (HERVs) are accounting for 8% of the human genome. These sequences are remnants from ancient germline infections by exogenous retroviruses. After million years of evolution and multiple integrations, HERVs have acquired many damages rendering them defective. At steady state, HERVs are mostly localized in the heterochromatin and silenced by methylation. Multiple conditions have been described to induce their reactivation, including auto-immune diseases and cancers. HERVs re-expression leads to RNA (simple and double-stranded) and DNA production (by reverse transcription), modulating the innate immune response. Some studies also argue for a role of HERVs in shaping the evolution of innate immunity, notably in the development of the interferon response. However, their exact role in the innate immune response, particularly in cancer, remains to be defined. In this review, we see how HERVs could be key-players in mounting an antitumor immune response. After a brief introduction on HERVs characteristics and biology, we review the different mechanisms by which HERVs can interact with the immune system, with a focus on the innate response. We then discuss the potential impact of HERVs expression on the innate immune response in cancer. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessReview
MAIT Cells Come to the Rescue in Cancer Immunotherapy?
Cancers 2020, 12(2), 413; https://doi.org/10.3390/cancers12020413 - 11 Feb 2020
Abstract
Recent progress in immunobiology has led to the observation that, among cells classically categorized as the typical representatives of the adaptive immune system, i.e., T cells, some possess the phenotype of innate cells. Invariant T cells are characterized by T cell receptors recognizing [...] Read more.
Recent progress in immunobiology has led to the observation that, among cells classically categorized as the typical representatives of the adaptive immune system, i.e., T cells, some possess the phenotype of innate cells. Invariant T cells are characterized by T cell receptors recognizing a limited range of non-peptide antigens, presented only in the context of particular molecules. Mucosal-associated invariant T cells (MAIT cells) are an example of such unconventional cells. In humans, they constitute between 1% and 8% of the peripheral blood T lymphocytes and are further enriched in mucosal tissues, mesenteric lymph nodes, and liver, where they can account for even 40% of all the T cells. MAIT cells recognize antigens in the context of major histocompatibility complex class I-related protein (MR1). Upon activation, they instantly release pro-inflammatory cytokines and mediate cytolytic function towards bacterially infected cells. As such, they have been a rapidly evolving research topic not only in the field of infectious diseases but also in the context of many chronic inflammatory diseases and, more recently, in immuno-oncology. Novel findings suggest that MAIT cells function could also be modulated by endogenous ligands and drugs, making them an attractive target for therapeutic approaches. In this review, we summarize the current understanding of MAIT cell biology, their role in health and disease and discuss their future potential in cancer immunotherapy. This is discussed through the prism of knowledge and experiences with invariant natural killer T cells (iNKT)—another prominent unconventional T cell subset that shares many features with MAIT cells. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessReview
Toll-like Receptors from the Perspective of Cancer Treatment
Cancers 2020, 12(2), 297; https://doi.org/10.3390/cancers12020297 - 27 Jan 2020
Abstract
Toll-like receptors (TLRs) represent a family of pattern recognition receptors that recognize certain pathogen-associated molecular patterns and damage-associated molecular patterns. TLRs are highly interesting to researchers including immunologists because of the involvement in various diseases including cancers, allergies, autoimmunity, infections, and inflammation. After [...] Read more.
Toll-like receptors (TLRs) represent a family of pattern recognition receptors that recognize certain pathogen-associated molecular patterns and damage-associated molecular patterns. TLRs are highly interesting to researchers including immunologists because of the involvement in various diseases including cancers, allergies, autoimmunity, infections, and inflammation. After ligand engagement, TLRs trigger multiple signaling pathways involving nuclear factor-κB (NF-κB), interferon-regulatory factors (IRFs), and mitogen-activated protein kinases (MAPKs) for the production of various cytokines that play an important role in diseases like cancer. TLR activation in immune as well as cancer cells may prevent the formation and growth of a tumor. Nonetheless, under certain conditions, either hyperactivation or hypoactivation of TLRs supports the survival and metastasis of a tumor. Therefore, the design of TLR-targeting agonists as well as antagonists is a promising immunotherapeutic approach to cancer. In this review, we mainly describe TLRs, their involvement in cancer, and their promising properties for anticancer drug discovery. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessReview
Natural Killer Cells as Allogeneic Effectors in Adoptive Cancer Immunotherapy
Cancers 2019, 11(6), 769; https://doi.org/10.3390/cancers11060769 - 03 Jun 2019
Cited by 15
Abstract
Natural killer (NK) cells are attractive within adoptive transfer settings in cancer immunotherapy due to their potential for allogeneic use; their alloreactivity is enhanced under conditions of killer immunoglobulin-like receptor (KIR) mismatch with human leukocyte antigen (HLA) ligands on cancer cells. In addition [...] Read more.
Natural killer (NK) cells are attractive within adoptive transfer settings in cancer immunotherapy due to their potential for allogeneic use; their alloreactivity is enhanced under conditions of killer immunoglobulin-like receptor (KIR) mismatch with human leukocyte antigen (HLA) ligands on cancer cells. In addition to this, NK cells are platforms for genetic modification, and proliferate in vivo for a shorter time relative to T cells, limiting off-target activation. Current clinical studies have demonstrated the safety and efficacy of allogeneic NK cell adoptive transfer therapies as a means for treatment of hematologic malignancies and, to a lesser extent, solid tumors. However, challenges associated with sourcing allogeneic NK cells have given rise to controversy over the contribution of NK cells to graft-versus-host disease (GvHD). Specifically, blood-derived NK cell infusions contain contaminating T cells, whose activation with NK-stimulating cytokines has been known to lead to heightened release of proinflammatory cytokines and trigger the onset of GvHD in vivo. NK cells sourced from cell lines and stem cells lack contaminating T cells, but can also lack many phenotypic characteristics of mature NK cells. Here, we discuss the available published evidence for the varying roles of NK cells in GvHD and, more broadly, their use in allogeneic adoptive transfer settings to treat various cancers. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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Open AccessReview
Tumor-Associated Neutrophils in Cancer: Going Pro
Cancers 2019, 11(4), 564; https://doi.org/10.3390/cancers11040564 - 19 Apr 2019
Cited by 21
Abstract
The progression of cancer is not only about the tumor cell itself, but also about other involved players including cancer cell recruited immune cells, their released pro-inflammatory factors, and the extracellular matrix. These players constitute the tumor microenvironment and play vital roles in [...] Read more.
The progression of cancer is not only about the tumor cell itself, but also about other involved players including cancer cell recruited immune cells, their released pro-inflammatory factors, and the extracellular matrix. These players constitute the tumor microenvironment and play vital roles in the cancer progression. Neutrophils—the most abundant white blood cells in the circulation system—constitute a significant part of the tumor microenvironment. Neutrophils play major roles linking inflammation and cancer and are actively involved in progression and metastasis. Additionally, recent data suggest that neutrophils could be considered one of the emerging targets for multiple cancer types. This review summarizes the most recent updates regarding neutrophil recruitments and functions in the tumor microenvironment as well as potential development of neutrophils-targeted putative therapeutic strategies. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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