Inhibition of STAT3 augments antitumor efficacy of anti-CTLA-4 treatment against prostate cancer

There is an urgent need for new treatment options in metastatic drug-resistant prostate cancer. Combining immunotherapy with other targeted therapies may be an effective strategy for advanced prostate cancer. In the present study, we sought to investigate to enhance the efficacy of anti-CTLA-4 thera...

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Autores principales: Witt, Kristina, Evans-Axelsson, Susan, Lundqvist, Andreas, Johansson, Martin, Bjartell, Anders, Hellsten, Rebecka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Original Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505385/
https://www.ncbi.nlm.nih.gov/pubmed/33786638
http://dx.doi.org/10.1007/s00262-021-02915-6
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author Witt, Kristina
Evans-Axelsson, Susan
Lundqvist, Andreas
Johansson, Martin
Bjartell, Anders
Hellsten, Rebecka
author_facet Witt, Kristina
Evans-Axelsson, Susan
Lundqvist, Andreas
Johansson, Martin
Bjartell, Anders
Hellsten, Rebecka
author_sort Witt, Kristina
collection PubMed
description There is an urgent need for new treatment options in metastatic drug-resistant prostate cancer. Combining immunotherapy with other targeted therapies may be an effective strategy for advanced prostate cancer. In the present study, we sought to investigate to enhance the efficacy of anti-CTLA-4 therapy against prostate cancer by the combination with STAT3 inhibition. Male C57BL6 mice were subcutaneously inoculated with the murine prostate cancer cell line RM-1. Tumor progression was monitored following treatment with vehicle, the small molecule STAT3 inhibitor GPB730, anti-CTLA-4 or GPB730 + anti-CTLA-4. Treatment with anti-CTLA-4 or anti-CTLA-4 + GPB730 significantly inhibited tumor growth and enhanced survival compared to vehicle. Combining anti-CTLA-4 treatment with GPB730 resulted in a significantly prolonged survival compared to anti-CTLA-4 alone. GPB730 significantly increased infiltration of CD45 + cells in tumors of anti-CTLA-4-treated mice compared to anti-CTLA-4 alone. The levels of tumor-infiltrating Tregs were significantly decreased and the CD8:Treg ratio significantly increased by GPB730 treatment in combination with anti-CTLA-4 compared to anti-CTLA-4 alone. Immunohistochemical analysis showed a significant increase in CD45-positive cells in anti-CTLA-4 and anti-CTLA-4 + GPB730-treated tumors compared to vehicle or GPB730 monotherapy. Plasma levels of IL10 were significantly increased by anti-CTLA-4 compared to vehicle but no increase was observed when combining anti-CTLA-4 with GPB730. In conclusion, STAT3 inhibition by GPB730 enhances the antitumoral activity of anti-CTLA-4 and decreases the intratumoral Treg frequency in a prostate cancer mouse model. These results support the combination of STAT3 inhibition with anti-CTLA-4 therapy to increase clinical responses in patients with prostate cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00262-021-02915-6.
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spelling pubmed-85053852021-10-19 Inhibition of STAT3 augments antitumor efficacy of anti-CTLA-4 treatment against prostate cancer Witt, Kristina Evans-Axelsson, Susan Lundqvist, Andreas Johansson, Martin Bjartell, Anders Hellsten, Rebecka Cancer Immunol Immunother Original Article There is an urgent need for new treatment options in metastatic drug-resistant prostate cancer. Combining immunotherapy with other targeted therapies may be an effective strategy for advanced prostate cancer. In the present study, we sought to investigate to enhance the efficacy of anti-CTLA-4 therapy against prostate cancer by the combination with STAT3 inhibition. Male C57BL6 mice were subcutaneously inoculated with the murine prostate cancer cell line RM-1. Tumor progression was monitored following treatment with vehicle, the small molecule STAT3 inhibitor GPB730, anti-CTLA-4 or GPB730 + anti-CTLA-4. Treatment with anti-CTLA-4 or anti-CTLA-4 + GPB730 significantly inhibited tumor growth and enhanced survival compared to vehicle. Combining anti-CTLA-4 treatment with GPB730 resulted in a significantly prolonged survival compared to anti-CTLA-4 alone. GPB730 significantly increased infiltration of CD45 + cells in tumors of anti-CTLA-4-treated mice compared to anti-CTLA-4 alone. The levels of tumor-infiltrating Tregs were significantly decreased and the CD8:Treg ratio significantly increased by GPB730 treatment in combination with anti-CTLA-4 compared to anti-CTLA-4 alone. Immunohistochemical analysis showed a significant increase in CD45-positive cells in anti-CTLA-4 and anti-CTLA-4 + GPB730-treated tumors compared to vehicle or GPB730 monotherapy. Plasma levels of IL10 were significantly increased by anti-CTLA-4 compared to vehicle but no increase was observed when combining anti-CTLA-4 with GPB730. In conclusion, STAT3 inhibition by GPB730 enhances the antitumoral activity of anti-CTLA-4 and decreases the intratumoral Treg frequency in a prostate cancer mouse model. These results support the combination of STAT3 inhibition with anti-CTLA-4 therapy to increase clinical responses in patients with prostate cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00262-021-02915-6. Springer Berlin Heidelberg 2021-03-31 2021 /pmc/articles/PMC8505385/ /pubmed/33786638 http://dx.doi.org/10.1007/s00262-021-02915-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Witt, Kristina
Evans-Axelsson, Susan
Lundqvist, Andreas
Johansson, Martin
Bjartell, Anders
Hellsten, Rebecka
Inhibition of STAT3 augments antitumor efficacy of anti-CTLA-4 treatment against prostate cancer
title Inhibition of STAT3 augments antitumor efficacy of anti-CTLA-4 treatment against prostate cancer
title_full Inhibition of STAT3 augments antitumor efficacy of anti-CTLA-4 treatment against prostate cancer
title_fullStr Inhibition of STAT3 augments antitumor efficacy of anti-CTLA-4 treatment against prostate cancer
title_full_unstemmed Inhibition of STAT3 augments antitumor efficacy of anti-CTLA-4 treatment against prostate cancer
title_short Inhibition of STAT3 augments antitumor efficacy of anti-CTLA-4 treatment against prostate cancer
title_sort inhibition of stat3 augments antitumor efficacy of anti-ctla-4 treatment against prostate cancer
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505385/
https://www.ncbi.nlm.nih.gov/pubmed/33786638
http://dx.doi.org/10.1007/s00262-021-02915-6
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