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CTLA-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous T cell responses in vitro

Dendritic cell (DC)-based immunotherapy has increased interest among anti-cancer immunotherapies. Nevertheless, the immunosuppressive mechanisms in the tumor milieu, e.g., inhibitory immune checkpoint molecules, have been implicated in diminishing the efficacy of DC-mediated anti-tumoral immune resp...

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Autores principales: Ghorbaninezhad, Farid, Masoumi, Javad, Bakhshivand, Mohammad, Baghbanzadeh, Amir, Mokhtarzadeh, Ahad, Kazemi, Tohid, Aghebati-Maleki, Leili, Shotorbani, Siamak Sandoghchian, Jafarlou, Mahdi, Brunetti, Oronzo, Santarpia, Mariacarmela, Baradaran, Behzad, Silvestris, Nicola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9376327/
https://www.ncbi.nlm.nih.gov/pubmed/35979362
http://dx.doi.org/10.3389/fimmu.2022.931316
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author Ghorbaninezhad, Farid
Masoumi, Javad
Bakhshivand, Mohammad
Baghbanzadeh, Amir
Mokhtarzadeh, Ahad
Kazemi, Tohid
Aghebati-Maleki, Leili
Shotorbani, Siamak Sandoghchian
Jafarlou, Mahdi
Brunetti, Oronzo
Santarpia, Mariacarmela
Baradaran, Behzad
Silvestris, Nicola
author_facet Ghorbaninezhad, Farid
Masoumi, Javad
Bakhshivand, Mohammad
Baghbanzadeh, Amir
Mokhtarzadeh, Ahad
Kazemi, Tohid
Aghebati-Maleki, Leili
Shotorbani, Siamak Sandoghchian
Jafarlou, Mahdi
Brunetti, Oronzo
Santarpia, Mariacarmela
Baradaran, Behzad
Silvestris, Nicola
author_sort Ghorbaninezhad, Farid
collection PubMed
description Dendritic cell (DC)-based immunotherapy has increased interest among anti-cancer immunotherapies. Nevertheless, the immunosuppressive mechanisms in the tumor milieu, e.g., inhibitory immune checkpoint molecules, have been implicated in diminishing the efficacy of DC-mediated anti-tumoral immune responses. Therefore, the main challenge is to overcome inhibitory immune checkpoint molecules and provoke efficient T-cell responses to antigens specifically expressed by cancerous cells. Among the inhibitory immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression on DCs diminishes their maturation and antigen presentation capability. Accordingly, we hypothesized that the expression of CTLA-4 on DCs inhibits the T cell-mediated anti-tumoral responses generated following the presentation of tumor antigens by DCs to T lymphocytes. In this study, we loaded colorectal cancer (CRC) cell lysate on DCs and inhibited the expression of CTLA-4 by small interfering RNA (siRNA) in them to investigate the DCs’ functional and phenotypical features, and T-cell mediated responses following DC/T cell co-culture. Our results demonstrated that blockade of CTLA-4 could promote stimulatory properties of DCs. In addition, CTLA-4 silenced CRC cell lysate-loaded DCs compared to the DCs without CTLA-4 silencing resulted in augmented T cell proliferation and cytokine production, i.e., IFN-γ and IL-4. Taken together, our findings suggest CTLA-4 silenced CRC cell lysate-loaded DCs as a promising therapeutic approach however further studies are needed before this strategy can be used in clinical practice.
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spelling pubmed-93763272022-08-16 CTLA-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous T cell responses in vitro Ghorbaninezhad, Farid Masoumi, Javad Bakhshivand, Mohammad Baghbanzadeh, Amir Mokhtarzadeh, Ahad Kazemi, Tohid Aghebati-Maleki, Leili Shotorbani, Siamak Sandoghchian Jafarlou, Mahdi Brunetti, Oronzo Santarpia, Mariacarmela Baradaran, Behzad Silvestris, Nicola Front Immunol Immunology Dendritic cell (DC)-based immunotherapy has increased interest among anti-cancer immunotherapies. Nevertheless, the immunosuppressive mechanisms in the tumor milieu, e.g., inhibitory immune checkpoint molecules, have been implicated in diminishing the efficacy of DC-mediated anti-tumoral immune responses. Therefore, the main challenge is to overcome inhibitory immune checkpoint molecules and provoke efficient T-cell responses to antigens specifically expressed by cancerous cells. Among the inhibitory immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression on DCs diminishes their maturation and antigen presentation capability. Accordingly, we hypothesized that the expression of CTLA-4 on DCs inhibits the T cell-mediated anti-tumoral responses generated following the presentation of tumor antigens by DCs to T lymphocytes. In this study, we loaded colorectal cancer (CRC) cell lysate on DCs and inhibited the expression of CTLA-4 by small interfering RNA (siRNA) in them to investigate the DCs’ functional and phenotypical features, and T-cell mediated responses following DC/T cell co-culture. Our results demonstrated that blockade of CTLA-4 could promote stimulatory properties of DCs. In addition, CTLA-4 silenced CRC cell lysate-loaded DCs compared to the DCs without CTLA-4 silencing resulted in augmented T cell proliferation and cytokine production, i.e., IFN-γ and IL-4. Taken together, our findings suggest CTLA-4 silenced CRC cell lysate-loaded DCs as a promising therapeutic approach however further studies are needed before this strategy can be used in clinical practice. Frontiers Media S.A. 2022-08-01 /pmc/articles/PMC9376327/ /pubmed/35979362 http://dx.doi.org/10.3389/fimmu.2022.931316 Text en Copyright © 2022 Ghorbaninezhad, Masoumi, Bakhshivand, Baghbanzadeh, Mokhtarzadeh, Kazemi, Aghebati-Maleki, Shotorbani, Jafarlou, Brunetti, Santarpia, Baradaran and Silvestris https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Ghorbaninezhad, Farid
Masoumi, Javad
Bakhshivand, Mohammad
Baghbanzadeh, Amir
Mokhtarzadeh, Ahad
Kazemi, Tohid
Aghebati-Maleki, Leili
Shotorbani, Siamak Sandoghchian
Jafarlou, Mahdi
Brunetti, Oronzo
Santarpia, Mariacarmela
Baradaran, Behzad
Silvestris, Nicola
CTLA-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous T cell responses in vitro
title CTLA-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous T cell responses in vitro
title_full CTLA-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous T cell responses in vitro
title_fullStr CTLA-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous T cell responses in vitro
title_full_unstemmed CTLA-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous T cell responses in vitro
title_short CTLA-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous T cell responses in vitro
title_sort ctla-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous t cell responses in vitro
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9376327/
https://www.ncbi.nlm.nih.gov/pubmed/35979362
http://dx.doi.org/10.3389/fimmu.2022.931316
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