Interleukin-2 is required for NKp30-dependent NK cell cytotoxicity by preferentially regulating NKp30 expression
Natural killer (NK) cells are key effectors in cancer immunosurveillance, eliminating a broad spectrum of cancer cells without major histocompatibility complex (MHC) specificity and graft-versus-host diseases (GvHD) risk. The use of allogeneic NK cell therapies from healthy donors has demonstrated f...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1388018/full |
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| author | Nayoung Kim Nayoung Kim Eunbi Yi Eunbi Lee Hyo Jin Park Hun Sik Kim Hun Sik Kim |
| author_facet | Nayoung Kim Nayoung Kim Eunbi Yi Eunbi Lee Hyo Jin Park Hun Sik Kim Hun Sik Kim |
| author_sort | Nayoung Kim |
| collection | DOAJ |
| description | Natural killer (NK) cells are key effectors in cancer immunosurveillance, eliminating a broad spectrum of cancer cells without major histocompatibility complex (MHC) specificity and graft-versus-host diseases (GvHD) risk. The use of allogeneic NK cell therapies from healthy donors has demonstrated favorable clinical efficacies in treating diverse cancers, particularly hematologic malignancies, but it requires cytokines such as IL-2 to primarily support NK cell persistence and expansion. However, the role of IL-2 in the regulation of activating receptors and the function of NK cells expanded for clinical trials is poorly understood and needs clarification for the full engagement of NK cells in cancer immunotherapy. Here, we demonstrated that IL-2 deprivation significantly impaired the cytotoxicity of primary expanded NK cells by preferentially downregulating NKp30 but not NKp46 despite their common adaptor requirement for expression and function. Using NK92 and IL-2-producing NK92MI cells, we observed that NKp30-mediated cytotoxicity against myeloid leukemia cells such as K562 and THP-1 cells expressing B7-H6, a ligand for NKp30, was severely impaired by IL-2 deprivation. Furthermore, IL-2 deficiency-mediated NK cell dysfunction was overcome by the ectopic overexpression of an immunostimulatory NKp30 isoform such as NKp30a or NKp30b. In particular, NKp30a overexpression in NK92 cells improved the clearance of THP-1 cells in vivo without IL-2 supplementation. Collectively, our results highlight the distinct role of IL-2 in the regulation of NKp30 compared to that of NKp46 and suggest NKp30 upregulation, as shown here by ectopic overexpression, as a viable modality to harness NK cells in cancer immunotherapy, possibly in combination with IL-2 immunocytokines. |
| first_indexed | 2024-04-24T07:57:34Z |
| format | Article |
| id | doaj.art-ca4661ead14c459fb22af5f3697066f3 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-24T07:57:34Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ca4661ead14c459fb22af5f3697066f32024-04-18T04:49:02ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-04-011510.3389/fimmu.2024.13880181388018Interleukin-2 is required for NKp30-dependent NK cell cytotoxicity by preferentially regulating NKp30 expressionNayoung Kim0Nayoung Kim1Eunbi Yi2Eunbi Lee3Hyo Jin Park4Hun Sik Kim5Hun Sik Kim6Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaAsan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaDepartment of Microbiology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaDepartment of Microbiology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaDepartment of Microbiology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaDepartment of Microbiology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaStem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaNatural killer (NK) cells are key effectors in cancer immunosurveillance, eliminating a broad spectrum of cancer cells without major histocompatibility complex (MHC) specificity and graft-versus-host diseases (GvHD) risk. The use of allogeneic NK cell therapies from healthy donors has demonstrated favorable clinical efficacies in treating diverse cancers, particularly hematologic malignancies, but it requires cytokines such as IL-2 to primarily support NK cell persistence and expansion. However, the role of IL-2 in the regulation of activating receptors and the function of NK cells expanded for clinical trials is poorly understood and needs clarification for the full engagement of NK cells in cancer immunotherapy. Here, we demonstrated that IL-2 deprivation significantly impaired the cytotoxicity of primary expanded NK cells by preferentially downregulating NKp30 but not NKp46 despite their common adaptor requirement for expression and function. Using NK92 and IL-2-producing NK92MI cells, we observed that NKp30-mediated cytotoxicity against myeloid leukemia cells such as K562 and THP-1 cells expressing B7-H6, a ligand for NKp30, was severely impaired by IL-2 deprivation. Furthermore, IL-2 deficiency-mediated NK cell dysfunction was overcome by the ectopic overexpression of an immunostimulatory NKp30 isoform such as NKp30a or NKp30b. In particular, NKp30a overexpression in NK92 cells improved the clearance of THP-1 cells in vivo without IL-2 supplementation. Collectively, our results highlight the distinct role of IL-2 in the regulation of NKp30 compared to that of NKp46 and suggest NKp30 upregulation, as shown here by ectopic overexpression, as a viable modality to harness NK cells in cancer immunotherapy, possibly in combination with IL-2 immunocytokines.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1388018/fullnatural killer cellIL-2NKp30NKp46acute myeloid leukemia |
| spellingShingle | Nayoung Kim Nayoung Kim Eunbi Yi Eunbi Lee Hyo Jin Park Hun Sik Kim Hun Sik Kim Interleukin-2 is required for NKp30-dependent NK cell cytotoxicity by preferentially regulating NKp30 expression Frontiers in Immunology natural killer cell IL-2 NKp30 NKp46 acute myeloid leukemia |
| title | Interleukin-2 is required for NKp30-dependent NK cell cytotoxicity by preferentially regulating NKp30 expression |
| title_full | Interleukin-2 is required for NKp30-dependent NK cell cytotoxicity by preferentially regulating NKp30 expression |
| title_fullStr | Interleukin-2 is required for NKp30-dependent NK cell cytotoxicity by preferentially regulating NKp30 expression |
| title_full_unstemmed | Interleukin-2 is required for NKp30-dependent NK cell cytotoxicity by preferentially regulating NKp30 expression |
| title_short | Interleukin-2 is required for NKp30-dependent NK cell cytotoxicity by preferentially regulating NKp30 expression |
| title_sort | interleukin 2 is required for nkp30 dependent nk cell cytotoxicity by preferentially regulating nkp30 expression |
| topic | natural killer cell IL-2 NKp30 NKp46 acute myeloid leukemia |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1388018/full |
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