Cargando…

Staphylococcal Enterotoxin C2 Mutant-Induced Antitumor Immune Response Is Controlled by CDC42/MLC2-Mediated Tumor Cell Stiffness

As a biological macromolecule, the superantigen staphylococcal enterotoxin C2 (SEC2) is one of the most potent known T-cell activators, and it induces massive cytotoxic granule production. With this property, SEC2 and its mutants are widely regarded as immunomodulating agents for cancer therapy. In...

Descripción completa

Detalles Bibliográficos
Autores principales: Fu, Xuanhe, Xu, Mingkai, Yu, Zhixiong, Gu, Wu, Zhang, Zhichun, Zhang, Bowen, Wang, Xiujuan, Su, Zhencheng, Zhang, Chenggang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380429/
https://www.ncbi.nlm.nih.gov/pubmed/37511553
http://dx.doi.org/10.3390/ijms241411796
_version_ 1785080191527157760
author Fu, Xuanhe
Xu, Mingkai
Yu, Zhixiong
Gu, Wu
Zhang, Zhichun
Zhang, Bowen
Wang, Xiujuan
Su, Zhencheng
Zhang, Chenggang
author_facet Fu, Xuanhe
Xu, Mingkai
Yu, Zhixiong
Gu, Wu
Zhang, Zhichun
Zhang, Bowen
Wang, Xiujuan
Su, Zhencheng
Zhang, Chenggang
author_sort Fu, Xuanhe
collection PubMed
description As a biological macromolecule, the superantigen staphylococcal enterotoxin C2 (SEC2) is one of the most potent known T-cell activators, and it induces massive cytotoxic granule production. With this property, SEC2 and its mutants are widely regarded as immunomodulating agents for cancer therapy. In a previous study, we constructed an MHC-II-independent mutant of SEC2, named ST-4, which exhibits enhanced immunocyte stimulation and antitumor activity. However, tumor cells have different degrees of sensitivity to SEC2/ST-4. The mechanisms of immune resistance to SEs in cancer cells have not been investigated. Herein, we show that ST-4 could activate more powerful human lymphocyte granule-based cytotoxicity than SEC2. The results of RNA-seq and atomic force microscopy (AFM) analysis showed that, compared with SKOV3 cells, the softer ES-2 cells could escape from SEC2/ST-4-induced cytotoxic T-cell-mediated apoptosis by regulating cell softness through the CDC42/MLC2 pathway. Conversely, after enhancing the stiffness of cancer cells by a nonmuscle myosin-II-specific inhibitor, SEC2/ST-4 exhibited a significant antitumor effect against ES-2 cells by promoting perforin-dependent apoptosis and the S-phase arrest. Taken together, these data suggest that cell stiffness could be a key factor of resistance to SEs in ovarian cancer, and our findings may provide new insight for SE-based tumor immunotherapy.
format Online
Article
Text
id pubmed-10380429
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-103804292023-07-29 Staphylococcal Enterotoxin C2 Mutant-Induced Antitumor Immune Response Is Controlled by CDC42/MLC2-Mediated Tumor Cell Stiffness Fu, Xuanhe Xu, Mingkai Yu, Zhixiong Gu, Wu Zhang, Zhichun Zhang, Bowen Wang, Xiujuan Su, Zhencheng Zhang, Chenggang Int J Mol Sci Article As a biological macromolecule, the superantigen staphylococcal enterotoxin C2 (SEC2) is one of the most potent known T-cell activators, and it induces massive cytotoxic granule production. With this property, SEC2 and its mutants are widely regarded as immunomodulating agents for cancer therapy. In a previous study, we constructed an MHC-II-independent mutant of SEC2, named ST-4, which exhibits enhanced immunocyte stimulation and antitumor activity. However, tumor cells have different degrees of sensitivity to SEC2/ST-4. The mechanisms of immune resistance to SEs in cancer cells have not been investigated. Herein, we show that ST-4 could activate more powerful human lymphocyte granule-based cytotoxicity than SEC2. The results of RNA-seq and atomic force microscopy (AFM) analysis showed that, compared with SKOV3 cells, the softer ES-2 cells could escape from SEC2/ST-4-induced cytotoxic T-cell-mediated apoptosis by regulating cell softness through the CDC42/MLC2 pathway. Conversely, after enhancing the stiffness of cancer cells by a nonmuscle myosin-II-specific inhibitor, SEC2/ST-4 exhibited a significant antitumor effect against ES-2 cells by promoting perforin-dependent apoptosis and the S-phase arrest. Taken together, these data suggest that cell stiffness could be a key factor of resistance to SEs in ovarian cancer, and our findings may provide new insight for SE-based tumor immunotherapy. MDPI 2023-07-22 /pmc/articles/PMC10380429/ /pubmed/37511553 http://dx.doi.org/10.3390/ijms241411796 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fu, Xuanhe
Xu, Mingkai
Yu, Zhixiong
Gu, Wu
Zhang, Zhichun
Zhang, Bowen
Wang, Xiujuan
Su, Zhencheng
Zhang, Chenggang
Staphylococcal Enterotoxin C2 Mutant-Induced Antitumor Immune Response Is Controlled by CDC42/MLC2-Mediated Tumor Cell Stiffness
title Staphylococcal Enterotoxin C2 Mutant-Induced Antitumor Immune Response Is Controlled by CDC42/MLC2-Mediated Tumor Cell Stiffness
title_full Staphylococcal Enterotoxin C2 Mutant-Induced Antitumor Immune Response Is Controlled by CDC42/MLC2-Mediated Tumor Cell Stiffness
title_fullStr Staphylococcal Enterotoxin C2 Mutant-Induced Antitumor Immune Response Is Controlled by CDC42/MLC2-Mediated Tumor Cell Stiffness
title_full_unstemmed Staphylococcal Enterotoxin C2 Mutant-Induced Antitumor Immune Response Is Controlled by CDC42/MLC2-Mediated Tumor Cell Stiffness
title_short Staphylococcal Enterotoxin C2 Mutant-Induced Antitumor Immune Response Is Controlled by CDC42/MLC2-Mediated Tumor Cell Stiffness
title_sort staphylococcal enterotoxin c2 mutant-induced antitumor immune response is controlled by cdc42/mlc2-mediated tumor cell stiffness
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380429/
https://www.ncbi.nlm.nih.gov/pubmed/37511553
http://dx.doi.org/10.3390/ijms241411796
work_keys_str_mv AT fuxuanhe staphylococcalenterotoxinc2mutantinducedantitumorimmuneresponseiscontrolledbycdc42mlc2mediatedtumorcellstiffness
AT xumingkai staphylococcalenterotoxinc2mutantinducedantitumorimmuneresponseiscontrolledbycdc42mlc2mediatedtumorcellstiffness
AT yuzhixiong staphylococcalenterotoxinc2mutantinducedantitumorimmuneresponseiscontrolledbycdc42mlc2mediatedtumorcellstiffness
AT guwu staphylococcalenterotoxinc2mutantinducedantitumorimmuneresponseiscontrolledbycdc42mlc2mediatedtumorcellstiffness
AT zhangzhichun staphylococcalenterotoxinc2mutantinducedantitumorimmuneresponseiscontrolledbycdc42mlc2mediatedtumorcellstiffness
AT zhangbowen staphylococcalenterotoxinc2mutantinducedantitumorimmuneresponseiscontrolledbycdc42mlc2mediatedtumorcellstiffness
AT wangxiujuan staphylococcalenterotoxinc2mutantinducedantitumorimmuneresponseiscontrolledbycdc42mlc2mediatedtumorcellstiffness
AT suzhencheng staphylococcalenterotoxinc2mutantinducedantitumorimmuneresponseiscontrolledbycdc42mlc2mediatedtumorcellstiffness
AT zhangchenggang staphylococcalenterotoxinc2mutantinducedantitumorimmuneresponseiscontrolledbycdc42mlc2mediatedtumorcellstiffness