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Biomedicines
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Modulation of Innate Immunity in Cancer Immunotherapy
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Modulation of Innate Immunity in Cancer Immunotherapy

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 20799

Special Issue Editors

Dr. Carlos Del Fresno Sánchez

E-Mail Website
Guest Editor
Hospital la Paz Health Research Institute, La Paz University Hospital, 28029 Madrid, Spain
Interests: innate immunity; cancer immunotherapy; tumor immunology; Candida; trained immunity
Dr. Eduardo Lopez-Collazo

E-Mail Website
Guest Editor
Hospital la Paz Institute for Health Research (IdiPAZ), Madrid, Spain
Interests: innate immunity; sepsis; tumor immunology; cell fusion; immunotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Immunotherapy holds a great hope as a therapeutic approach against cancer. It aims to generate potent immune responses against cancer cells. Notably, the use of immune checkpoint inhibitors (ICIs) has demonstrated durable responses in patients with various malignancies. In fact, ICI-based treatments such as anti-PD-1/PD-L1, have already been approved for the treatment of some cancers, while CAR-T cells are attracting great attention.

A number of these therapeutic strategies are based on the activation of T cell-mediated responses. However, it is well known that tumor-infiltrating macrophages are critical mediators of innate immune responses against tumors and can either oppose or support them because of their plasticity. Therefore, harnessing innate immune responses to trigger subsequent T cell-mediated immunogenic responses is becoming a prominent new strategy in cancer immunotherapy. Along these lines, the activation of innate immunoreceptors overcomes resistance to anti-PD-1 immunotherapy, and immunotherapies can be boosted by targeted reprogramming of macrophages.

Of note, certain stimuli such as bacille Calmette-Guerin (BCG) tuberculosis vaccine and fungal ß-glucan can trigger trained immunity (TI) in macrophages, natural killer cells, and dendritic cells. This process indicates the capacity of innate cells to develop memory, generating enhanced inflammatory responses after a first activation. Remarkably, TI has been proven to be efficient against cancer and to boost ICI-based therapies in mice. These data reinforce the relevance of innate immunity for durable anti-tumor responses.

This Special Issue aims to present the current knowledge about the role of innate immune cells in cancer immunotherapy, including cutting-edge new findings in this field.

Dr. Carlos del Fresno Sánchez
Dr. Eduardo Lopez-Collazo
Guest Editors

Manuscript Submission Information

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

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 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.

Keywords

  • Tumor-infiltrating/associated macrophages
  • Macrophage/monocyte reprogramming
  • Trained immunity
  • Innate adjuvants
  • Myeloid development upon cancer
  • Immunogenic dendritic cells
  • NK cells in cancer immunotherapy
  • Myeloid plasticity in cancer immunotherapy

Published Papers (7 papers)

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Research

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12 pages, 1522 KiB  
Communication
Identification of sSIGLEC5 and sLAG3 as New Relapse Predictors in Lung Cancer
by Karla Montalbán-Hernández, José Carlos Casalvilla-Dueñas, Patricia Cruz-Castellanos, Laura Gutierrez-Sainz, Roberto Lozano-Rodríguez, José Avendaño-Ortiz, Carlos del Fresno, Javier de Castro-Carpeño and Eduardo López-Collazo
Biomedicines 2022, 10(5), 1047; https://doi.org/10.3390/biomedicines10051047 - 30 Apr 2022
Cited by 3 | Viewed by 2047
Abstract
Lung cancer (LC) continues to be the leading cause of cancer-related deaths in both men and women worldwide. After complete tumour resection, around half of the patients suffer from disease relapse, emphasising the critical need for robust relapse predictors in this disease. In [...] Read more.
Lung cancer (LC) continues to be the leading cause of cancer-related deaths in both men and women worldwide. After complete tumour resection, around half of the patients suffer from disease relapse, emphasising the critical need for robust relapse predictors in this disease. In search of such biomarkers, 83 patients with non-microcytic lung cancer and 67 healthy volunteers were studied. Pre-operative levels of sSIGLEC5 along with other soluble immune-checkpoints were measured and correlated with their clinical outcome. Soluble SIGLEC5 (sSIGLEC5) levels were higher in plasma from patients with LC compared with healthy volunteers. Looking into those patients who suffered relapse, sSIGLEC5 and sLAG3 were found to be strong relapse predictors. Following a binary logistic regression model, a sSIGLEC5 + sLAG3 score was established for disease relapse prediction (area under the curve 0.8803, 95% confidence intervals 0.7955–0.9652, cut-off > 2.782) in these patients. Based on score cut-off, a Kaplan–Meier analysis showed that patients with high sSIGLEC5 + sLAG3 score had significantly shorter relapse-free survival (p ≤ 0.0001) than those with low sSIGLEC5 + sLAG3 score.Our study suggests that pre-operative sSIGLEC5 + sLAG3 score is a robust relapse predictor in LC patients. Full article
(This article belongs to the Special Issue Modulation of Innate Immunity in Cancer Immunotherapy)
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14 pages, 6521 KiB  
Article
Enpp2 Expression by Dendritic Cells Is a Key Regulator in Migration
by Jun-Ho Lee, So-Yeon Choi, Soo-Yeoun Park, Nam-Chul Jung, Kyung-Eun Noh, Ji-Hee Nam, Ji-Soo Oh, Hyun-Ji Choi, Ji-Su Jang, Ji-Young Yoo, Jie-Young Song, Han Geuk Seo and Dae-Seog Lim
Biomedicines 2021, 9(11), 1727; https://doi.org/10.3390/biomedicines9111727 - 19 Nov 2021
Cited by 5 | Viewed by 2139
Abstract
Enpp2 is an enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which exhibits a wide variety of biological functions. Here, we examined the biological effects of Enpp2 on dendritic cells (DCs), which are specialized antigen-presenting cells (APCs) characterized by [...] Read more.
Enpp2 is an enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which exhibits a wide variety of biological functions. Here, we examined the biological effects of Enpp2 on dendritic cells (DCs), which are specialized antigen-presenting cells (APCs) characterized by their ability to migrate into secondary lymphoid organs and activate naïve T-cells. DCs were generated from bone marrow progenitors obtained from C57BL/6 mice. Enpp2 levels in DCs were regulated using small interfering (si)RNA or recombinant Enpp2. Expression of Enpp2 in LPS-stimulated mature (m)DCs was high, however, knocking down Enpp2 inhibited mDC function. In addition, the migratory capacity of mDCs increased after treatment with rmEnpp2; this phenomenon was mediated via the RhoA-mediated signaling pathway. Enpp2-treated mDCs showed a markedly increased capacity to migrate to lymph nodes in vivo. These findings strongly suggest that Enpp2 is necessary for mDC migration capacity, thereby increasing our understanding of DC biology. We postulate that regulating Enpp2 improves DC migration to lymph nodes, thus improving the effectiveness of cancer vaccines based on DC. Full article
(This article belongs to the Special Issue Modulation of Innate Immunity in Cancer Immunotherapy)
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18 pages, 3518 KiB  
Article
Irradiation Mediates IFNα and CXCL9 Expression in Non-Small Cell Lung Cancer to Stimulate CD8+ T Cells Activity and Migration toward Tumors
by Chun-Chia Cheng, Yi-Fang Chang, Ai-Sheng Ho, Zong-Lin Sie, Jung-Shan Chang, Cheng-Liang Peng and Chun-Chao Chang
Biomedicines 2021, 9(10), 1349; https://doi.org/10.3390/biomedicines9101349 - 29 Sep 2021
Cited by 10 | Viewed by 3049
Abstract
Irradiation-broken DNA fragments increase type I interferon and chemokines secretion in tumor cells. Since radiotherapy may augment tumor immunotherapy, we hypothesize that the chemokines increased by irradiation could recruit CD8+ T cells to suppress tumor proliferation. This study intended to unveil the [...] Read more.
Irradiation-broken DNA fragments increase type I interferon and chemokines secretion in tumor cells. Since radiotherapy may augment tumor immunotherapy, we hypothesize that the chemokines increased by irradiation could recruit CD8+ T cells to suppress tumor proliferation. This study intended to unveil the secreted factors activating and recruiting CD8+ T cells in non-small-cell lung cancer (NSCLC). EGFR-positive A549 was selected and treated by X-irradiation (IR) to identify the overexpression of chemokines associated to CD8+ T cell cytotoxicity and recruitment. A transwell assay with Alexa 488-labeled CD8+ T cells was used to evaluate CD8+ T cell motility in vitro. A nuclear imaging platform by In111-labeled nivolumab was used to track CD8+ T cells homing to tumors in vivo. The activation markers GZMB, PRF-1, and IFNγ, migration marker CD183 (CXCR3), and inhibitory marker CD274 (PD-1), were measured and compared in CD8+ T cells with A549 co-cultured, chemokines treated, and patients with late-stage lung cancer. We found that IR not only suppressed A549 proliferation but also induced IFNα and CXCL9 expression (p < 0.05). IFNα majorly increased IFNγ levels in CD8+ T cells (p < 0.05) and synergistically with CXCL9 enhanced CD8+ T cell migration in vitro (p < 0.05). We found that CXCR3 and PD-1 were down-regulated and up-regulated, respectively, in the peripheral blood CD8+ T cells in patients with lung cancer (n = 4 vs. healthy n = 3, both p < 0.05), which exhibited reduction of cell motility (p < 0.05). The in vivo nuclear imaging data indicated highly CD8+ T cells migrated to A549-induced tumors. In addition, we demonstrated that healthy PBMCs significantly suppressed the parallel tumor growth (p < 0.05) and the radioresistant tumor growth in the tumor xenograft mice (p < 0.05), but PBMCs from patients with lung cancer had lost the anti-tumor capacity. We demonstrated that IR induced IFNα and CXCL9 expression in A549 cells, leading to CD8+ T cell migration. This study unveiled a potential mechanism for radiotherapy to activate and recruit CD8+ T cells to suppress lung tumors. Full article
(This article belongs to the Special Issue Modulation of Innate Immunity in Cancer Immunotherapy)
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18 pages, 4280 KiB  
Article
Evaluation of β-Catenin Inhibition of Axitinib and Nitazoxanide in Human Monocyte-Derived Dendritic Cells
by Waqas Azeem, Ragnhild Maukon Bakke, Benjamin Gabriel, Silke Appel, Anne Margrete Øyan and Karl-Henning Kalland
Biomedicines 2021, 9(8), 949; https://doi.org/10.3390/biomedicines9080949 - 3 Aug 2021
Cited by 1 | Viewed by 2078
Abstract
Modulation of β-catenin signaling has attractive therapeutic potential in cancer immunotherapy. Several studies have found that β-catenin can mediate immune evasion in cancer and promote anti-inflammatory features of antigen-presenting dendritic cells. Many small molecular compounds that inhibit Wnt/β-catenin signaling are currently in clinical [...] Read more.
Modulation of β-catenin signaling has attractive therapeutic potential in cancer immunotherapy. Several studies have found that β-catenin can mediate immune evasion in cancer and promote anti-inflammatory features of antigen-presenting dendritic cells. Many small molecular compounds that inhibit Wnt/β-catenin signaling are currently in clinical development, but none have entered routine clinical use. New inhibitors of β-catenin signaling are consequently desirable. Here, we have tested, in monocyte-derived dendritic cells, the effects of two small molecular compounds, axitinib and nitazoxanide, that previously have been discovered to inhibit β-catenin signaling in colon cancer cells. Immature and lipopolysaccharide-matured dendritic cells prepared from healthy blood donor buffy coats were stimulated with 6-bromoindirubin-3′-oxime (6-BIO) to boost basal β-catenin activity, and the effects of axitinib and nitazoxanide were compared with the commercial β-catenin inhibitor ICG-001. Assays, including genome-wide RNA-sequencing, indicated that neither axitinib nor nitazoxanide demonstrated considerable β-catenin inhibition. Both compounds were found to be less toxic to monocyte-derived dendritic cells than either 6-BIO or ICG-001. Axitinib stimulated several aspects of dendritic cell function, such as IL12-p70 secretion, and counteracted IL-10 secretion, according to the present study. However, neither axitinib nor nitazoxanide were found to be efficient β-catenin inhibitors in monocyte-derived dendritic cells. Full article
(This article belongs to the Special Issue Modulation of Innate Immunity in Cancer Immunotherapy)
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14 pages, 3384 KiB  
Article
TGF-β Increases MFGE8 Production in Myeloid-Derived Suppressor Cells to Promote B16F10 Melanoma Metastasis
by Heejin Lim, Taewoo Yang, Wongeun Lee and Sung-Gyoo Park
Biomedicines 2021, 9(8), 896; https://doi.org/10.3390/biomedicines9080896 - 26 Jul 2021
Cited by 4 | Viewed by 3044
Abstract
There is growing evidence that myeloid-derived suppressor cells (MDSCs) are directly involved in all stages leading to metastasis. Many mechanisms for this effect have been proposed, but mechanisms of coregulation between tumor cells and MDSCs remain poorly understood. In this study, we demonstrate [...] Read more.
There is growing evidence that myeloid-derived suppressor cells (MDSCs) are directly involved in all stages leading to metastasis. Many mechanisms for this effect have been proposed, but mechanisms of coregulation between tumor cells and MDSCs remain poorly understood. In this study, we demonstrate that MDSCs are a source of milk fat globule-epidermal growth factor (EGF) factor 8 (MFGE8), which is known to be involved in tumor metastasis. Interestingly, TGF-β, an abundant cytokine in the tumor microenvironment (TME), increased MFGE8 production by MDSCs. In addition, co-culturing MDSCs with B16F10 melanoma cells increased B16F10 cell migration, while MFGE8 neutralization decreased their migration. Taken together, these findings suggest that MFGE8 is an important effector molecule through which MDSCs promote tumor metastasis, and the TME positively regulates MFGE8 production by MDSCs through TGF-β. Full article
(This article belongs to the Special Issue Modulation of Innate Immunity in Cancer Immunotherapy)
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Review

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41 pages, 1482 KiB  
Review
The War Is on: The Immune System against Glioblastoma—How Can NK Cells Drive This Battle?
by Lucas Henrique Rodrigues da Silva, Luana Correia Croda Catharino, Viviane Jennifer da Silva, Gabriela Coeli Menezes Evangelista and José Alexandre Marzagão Barbuto
Biomedicines 2022, 10(2), 400; https://doi.org/10.3390/biomedicines10020400 - 8 Feb 2022
Cited by 5 | Viewed by 3806
Abstract
Natural killer (NK) cells are innate lymphocytes that play an important role in immunosurveillance, acting alongside other immune cells in the response against various types of malignant tumors and the prevention of metastasis. Since their discovery in the 1970s, they have been thoroughly [...] Read more.
Natural killer (NK) cells are innate lymphocytes that play an important role in immunosurveillance, acting alongside other immune cells in the response against various types of malignant tumors and the prevention of metastasis. Since their discovery in the 1970s, they have been thoroughly studied for their capacity to kill neoplastic cells without the need for previous sensitization, executing rapid and robust cytotoxic activity, but also helper functions. In agreement with this, NK cells are being exploited in many ways to treat cancer. The broad arsenal of NK-based therapies includes adoptive transfer of in vitro expanded and activated cells, genetically engineered cells to contain chimeric antigen receptors (CAR-NKs), in vivo stimulation of NK cells (by cytokine therapy, checkpoint blockade therapies, etc.), and tumor-specific antibody-guided NK cells, among others. In this article, we review pivotal aspects of NK cells’ biology and their contribution to immune responses against tumors, as well as providing a wide perspective on the many antineoplastic strategies using NK cells. Finally, we also discuss those approaches that have the potential to control glioblastoma—a disease that, currently, causes inevitable death, usually in a short time after diagnosis. Full article
(This article belongs to the Special Issue Modulation of Innate Immunity in Cancer Immunotherapy)
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18 pages, 328 KiB  
Review
Innate Immune Mechanisms and Immunotherapy of Myeloid Malignancies
by Sara Small, Yazan Numan and Leonidas C. Platanias
Biomedicines 2021, 9(11), 1631; https://doi.org/10.3390/biomedicines9111631 - 6 Nov 2021
Cited by 3 | Viewed by 3015
Abstract
Similar to other cancers, myeloid malignancies are thought to subvert the immune system during their development. This subversion occurs via both malignant cell-autonomous and non-autonomous mechanisms and involves manipulation of the innate and adaptive immune systems. Multiple strategies are being studied to rejuvenate, [...] Read more.
Similar to other cancers, myeloid malignancies are thought to subvert the immune system during their development. This subversion occurs via both malignant cell-autonomous and non-autonomous mechanisms and involves manipulation of the innate and adaptive immune systems. Multiple strategies are being studied to rejuvenate, redirect, or re-enforce the immune system in order to fight off myeloid malignancies. So far, the most successful strategies include interferon treatment and antibody-based therapies, though chimeric antigen receptor (CAR) cells and immune checkpoint inhibitors are also promising therapies. In this review, we discuss the inherent immune mechanisms of defense against myeloid malignancies, currently-approved agents, and agents under investigation. Overall, we evaluate the efficacy and potential of immuno-oncology in the treatment of myeloid malignancies. Full article
(This article belongs to the Special Issue Modulation of Innate Immunity in Cancer Immunotherapy)
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