In Vitro Evaluation of CD276-CAR NK-92 Functionality, Migration and Invasion Potential in the Presence of Immune Inhibitory Factors of the Tumor Microenvironment
| Autor: | Kenneth Chun-Ho Chan, Rupert Handgretinger, Sabine Schleicher, Caroline Baden, Guillermo Ureña-Bailén, Stefan Grote, Markus Mezger |
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| Rok vydání: | 2021 |
| Předmět: |
Cytotoxicity
Immunologic B7 Antigens Skin Neoplasms QH301-705.5 medicine.medical_treatment In Vitro Techniques Immunotherapy Adoptive Article Immune system NK-92 Antigen Antigens Neoplasm Cell Movement Cell Line Tumor immune therapy medicine Tumor Microenvironment melanoma Cytotoxic T cell Humans Neoplasm Invasiveness Lactic Acid CD276 Biology (General) Hypoxia CRISPR/Cas9 Immunosuppression Therapy Tumor microenvironment Receptors Chimeric Antigen chimeric antigen receptor business.industry Melanoma Lentivirus General Medicine Immunotherapy Fibroblasts Hydrogen-Ion Concentration medicine.disease Chimeric antigen receptor Gene Expression Regulation Neoplastic Killer Cells Natural B7-H3 Immune System Cancer research CRISPR-Cas Systems business Immunosuppressive Agents |
| Zdroj: | Cells Volume 10 Issue 5 Cells, Vol 10, Iss 1020, p 1020 (2021) |
| ISSN: | 2073-4409 |
| Popis: | Background: Melanoma is the most lethal of all skin-related cancers with incidences continuously rising. Novel therapeutic approaches are urgently needed, especially for the treatment of metastasizing or therapy-resistant melanoma. CAR-modified immune cells have shown excellent results in treating hematological malignancies and might represent a new treatment strategy for refractory melanoma. However, solid tumors pose some obstacles for cellular immunotherapy, including the identification of tumor-specific target antigens, insufficient homing and infiltration of immune cells as well as immune cell dysfunction in the immunosuppressive tumor microenvironment (TME). Methods: In order to investigate whether CAR NK cell-based immunotherapy can overcome the obstacles posed by the TME in melanoma, we generated CAR NK-92 cells targeting CD276 (B7-H3) which is abundantly expressed in solid tumors, including melanoma, and tested their effectivity in vitro in the presence of low pH, hypoxia and other known factors of the TME influencing anti-tumor responses. Moreover, the CRISPR/Cas9-induced disruption of the inhibitory receptor NKG2A was assessed for its potential enhancement of NK-92-mediated anti-tumor activity. Results: CD276-CAR NK-92 cells induced specific cytolysis of melanoma cell lines while being able to overcome a variety of the immunosuppressive effects normally exerted by the TME. NKG2A knock-out did not further improve CAR NK-92 cell-mediated cytotoxicity. Conclusions: The strong cytotoxic effect of a CD276-specific CAR in combination with an “off-the-shelf” NK-92 cell line not being impaired by some of the most prominent negative factors of the TME make CD276-CAR NK-92 cells a promising cellular product for the treatment of melanoma and beyond. |
| Databáze: | OpenAIRE |
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