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Cancers
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Unnatural Killers for Immunotherapy: Harnessing NK Cells and Their Diversity...
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Unnatural Killers for Immunotherapy: Harnessing NK Cells and Their Diversity in the Tumor Microenvironment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 6625

Special Issue Editors

Dr. Massimo Vitale

E-Mail Website
Guest Editor
UO Immunologia, IRCCS Ospedale Policlinico San Martino Genova, 16132 Genoa, Italy
Interests: tumor microenvironment; tumor infiltrating immune cells; NK cells
Prof. Dr. Claudia Cantoni

E-Mail Website
Guest Editor
General Pathology Section, Department of Experimental Medicine, University of Genoa, 16126 Genoa, Italy
Interests: immunology; natural killer (NK) cells; tumor microenvironment; interactions between NK cells and virus infected cells
Prof. Dr. Simona Sivori

E-Mail Website
Guest Editor
Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy
Interests: human natural killer cells; NK cell receptors; natural cytotoxicity receptors; KIRs; CAR-NK; tumor-associated NK cells
Prof. Dr. Daniel A. Vallera

E-Mail Website
Guest Editor
Department of Radiation Oncology, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
Interests: cancer immunotherapy; leukemia; molecular therapeutics; targeted cancer therapy; tumor immunology; targeted therapy; antibody therapy; car T cells; bispecific antibodies (BsAbs)

Special Issue Information

Dear Colleagues,

NK cells have generated tremendous academic and commercial interest in the field of cancer immunotherapy as the general belief is they represent a reservoir of unmet clinical potential. “Natural killer cells” have long been recognized as important players in immunosurveillance and robust effectors of antibody dependent cell mediated cytotoxicity (ADCC). The term “unnatural killer cells” in our title refers to the explosion of NK cell papers describing either direct genetic manipulation of NK cells (for example CAR-NK) or indirect manipulation via genetically engineered antibody/cytokines to achieve better levels of ADCC and tumor killing. Currently, it is believed that a better understanding the complexity of receptor/ligand regulation in NK activation/inhibition, the diverse nature of NK cell subpopulations, and role of the tumor microenvironment in influencing NK anti-cancer responses will instruct future drug development and lead to better targeting strategies. For this Special Issue, we welcome original and review papers that deal with these important areas. We particularly invite papers that provide insight to connect NK cell diversity, the engineering of their function, and the tumor microenvironment in the design of future immunotherapeutic approaches.

We look forward to receiving your contributions.

Dr. Massimo Vitale
Prof. Dr. Claudia Cantoni
Prof. Dr. Simona Sivori
Prof. Dr. Daniel A. Vallera
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 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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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

  • engineered antibody
  • engineered cytokines
  • engineered NK cells
  • NK engagers
  • CAR-NK cells
  • tumor microenvironment
  • NK cell-based immunotherapy
  • ADCC
  • NK cell diversity

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Published Papers (2 papers)

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Research

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20 pages, 5409 KiB  
Article
Next-Generation CEA-CAR-NK-92 Cells against Solid Tumors: Overcoming Tumor Microenvironment Challenges in Colorectal Cancer
by Alexander Sebastian Franzén, Abdelhadi Boulifa, Clarissa Radecke, Sebastian Stintzing, Martin J. Raftery and Gabriele Pecher
Cancers 2024, 16(2), 388; https://doi.org/10.3390/cancers16020388 - 16 Jan 2024
Cited by 5 | Viewed by 3088
Abstract
Colorectal carcinoma (CRC) presents a formidable medical challenge, demanding innovative therapeutic strategies. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy has emerged as a promising alternative to CAR T-cell therapy for cancer. A suitable tumor antigen target on CRC is carcinoembryonic antigen [...] Read more.
Colorectal carcinoma (CRC) presents a formidable medical challenge, demanding innovative therapeutic strategies. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy has emerged as a promising alternative to CAR T-cell therapy for cancer. A suitable tumor antigen target on CRC is carcinoembryonic antigen (CEA), given its widespread expression and role in tumorigenesis and metastasis. CEA is known to be prolifically shed from tumor cells in a soluble form, thus hindering CAR recognition of tumors and migration through the TME. We have developed a next-generation CAR construct exclusively targeting cell-associated CEA, incorporating a PD1-checkpoint inhibitor and a CCR4 chemokine receptor to enhance homing and infiltration of the CAR-NK-92 cell line through the TME, and which does not induce fratricidal killing of CAR-NK-92-cells. To evaluate this therapeutic approach, we harnessed intricate 3D multicellular tumor spheroid models (MCTS), which emulate key elements of the TME. Our results demonstrate the effective cytotoxicity of CEA-CAR-NK-92 cells against CRC in colorectal cell lines and MCTS models. Importantly, minimal off-target activity against non-cancerous cell lines underscores the precision of this therapy. Furthermore, the integration of the CCR4 migration receptor augments homing by recognizing target ligands, CCL17 and CCL22. Notably, our CAR design results in no significant trogocytosis-induced fratricide. In summary, the proposed CEA-targeting CAR-NK cell therapy could offer a promising solution for CRC treatment, combining precision and efficacy in a tailored approach. Full article
(This article belongs to the Special Issue Unnatural Killers for Immunotherapy: Harnessing NK Cells and Their Diversity in the Tumor Microenvironment)
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Review

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28 pages, 3021 KiB  
Review
Natural Killer T Cell Diversity and Immunotherapy
by Eduardo I. Tognarelli, Cristián Gutiérrez-Vera, Pablo A. Palacios, Ignacio A. Pasten-Ferrada, Fernanda Aguirre-Muñoz, Daniel A. Cornejo, Pablo A. González and Leandro J. Carreño
Cancers 2023, 15(24), 5737; https://doi.org/10.3390/cancers15245737 - 7 Dec 2023
Cited by 5 | Viewed by 2857
Abstract
Invariant natural killer T cells (iNKTs), a type of unconventional T cells, share features with NK cells and have an invariant T cell receptor (TCR), which recognizes lipid antigens loaded on CD1d molecules, a major histocompatibility complex class I (MHC-I)-like protein. This interaction [...] Read more.
Invariant natural killer T cells (iNKTs), a type of unconventional T cells, share features with NK cells and have an invariant T cell receptor (TCR), which recognizes lipid antigens loaded on CD1d molecules, a major histocompatibility complex class I (MHC-I)-like protein. This interaction produces the secretion of a wide array of cytokines by these cells, including interferon gamma (IFN-γ) and interleukin 4 (IL-4), allowing iNKTs to link innate with adaptive responses. Interestingly, molecules that bind CD1d have been identified that enable the modulation of these cells, highlighting their potential pro-inflammatory and immunosuppressive capacities, as required in different clinical settings. In this review, we summarize key features of iNKTs and current understandings of modulatory α-galactosylceramide (α-GalCer) variants, a model iNKT cell activator that can shift the outcome of adaptive immune responses. Furthermore, we discuss advances in the development of strategies that modulate these cells to target pathologies that are considerable healthcare burdens. Finally, we recapitulate findings supporting a role for iNKTs in infectious diseases and tumor immunotherapy. Full article
(This article belongs to the Special Issue Unnatural Killers for Immunotherapy: Harnessing NK Cells and Their Diversity in the Tumor Microenvironment)
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