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Small-molecule PTPN2 Inhibitors Sensitize Resistant Melanoma to Anti-PD-1 Immunotherapy

Although immune checkpoint inhibitors targeting T-cell immunoregulatory proteins have revolutionized cancer treatment, they are effective only in a limited number of patients, and new strategies are needed to enhance tumor responses to immunotherapies. Deletion of protein tyrosine phosphatase non-re...

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Autores principales: Zhu, Zhouting, Tang, Rachel, Huff, Sarah, Kummetha, Indrasena Reddy, Wang, Lingling, Li, Na, Rana, Tariq M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035454/
https://www.ncbi.nlm.nih.gov/pubmed/36968224
http://dx.doi.org/10.1158/2767-9764.CRC-21-0186
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author Zhu, Zhouting
Tang, Rachel
Huff, Sarah
Kummetha, Indrasena Reddy
Wang, Lingling
Li, Na
Rana, Tariq M.
author_facet Zhu, Zhouting
Tang, Rachel
Huff, Sarah
Kummetha, Indrasena Reddy
Wang, Lingling
Li, Na
Rana, Tariq M.
author_sort Zhu, Zhouting
collection PubMed
description Although immune checkpoint inhibitors targeting T-cell immunoregulatory proteins have revolutionized cancer treatment, they are effective only in a limited number of patients, and new strategies are needed to enhance tumor responses to immunotherapies. Deletion of protein tyrosine phosphatase non-receptor type 2 (Ptpn2), a regulator of growth factor and cytokine signaling pathways, has been shown to sensitize murine B16F10 melanoma cells to IFNγ and anti-PD-1 immunotherapy. Here, we investigated the potential therapeutic utility of small-molecule PTPN2 inhibitors. Ten inhibitors were synthesized on the basis of in silico modeling and structure-based design and functionally tested in vitro and in vivo. We show that the inhibitors had little effect on B16F10 cells alone, but effectively sensitized the tumor cells to IFNγ treatment in vitro and to anti-PD-1 therapy in vivo. Under both conditions, Ptpn2 inhibitor cotreatment suppressed B16F10 cell growth and enhanced Stat1 phosphorylation and expression of IFNγ response genes. In vivo, PTPN2 inhibitor cotreatment significantly reduced melanoma and colorectal tumor growth and enhanced mouse survival compared with anti-PD-1 treatment alone, and this was accompanied by increased tumor infiltration by granzyme B(+) CD8(+) T cells. Similar results were obtained with representative murine and human colon cancer and lung cancer cell lines. Collectively, these results demonstrate that small-molecule inhibitors of PTPN2 may have clinical utility as sensitizing agents for immunotherapy-resistant cancers. SIGNIFICANCE: To enhance the effectiveness of immunotherapies in resistant or nonresponsive cancers, it is important to develop inhibitors of enzymes that negatively influence the outcome of treatments. We have designed and evaluated small-molecule inhibitors of PTPN2 demonstrating that these compounds may have clinical utility as sensitizing agents for immunotherapy-resistant cancers.
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spelling pubmed-100354542023-03-24 Small-molecule PTPN2 Inhibitors Sensitize Resistant Melanoma to Anti-PD-1 Immunotherapy Zhu, Zhouting Tang, Rachel Huff, Sarah Kummetha, Indrasena Reddy Wang, Lingling Li, Na Rana, Tariq M. Cancer Res Commun Research Article Although immune checkpoint inhibitors targeting T-cell immunoregulatory proteins have revolutionized cancer treatment, they are effective only in a limited number of patients, and new strategies are needed to enhance tumor responses to immunotherapies. Deletion of protein tyrosine phosphatase non-receptor type 2 (Ptpn2), a regulator of growth factor and cytokine signaling pathways, has been shown to sensitize murine B16F10 melanoma cells to IFNγ and anti-PD-1 immunotherapy. Here, we investigated the potential therapeutic utility of small-molecule PTPN2 inhibitors. Ten inhibitors were synthesized on the basis of in silico modeling and structure-based design and functionally tested in vitro and in vivo. We show that the inhibitors had little effect on B16F10 cells alone, but effectively sensitized the tumor cells to IFNγ treatment in vitro and to anti-PD-1 therapy in vivo. Under both conditions, Ptpn2 inhibitor cotreatment suppressed B16F10 cell growth and enhanced Stat1 phosphorylation and expression of IFNγ response genes. In vivo, PTPN2 inhibitor cotreatment significantly reduced melanoma and colorectal tumor growth and enhanced mouse survival compared with anti-PD-1 treatment alone, and this was accompanied by increased tumor infiltration by granzyme B(+) CD8(+) T cells. Similar results were obtained with representative murine and human colon cancer and lung cancer cell lines. Collectively, these results demonstrate that small-molecule inhibitors of PTPN2 may have clinical utility as sensitizing agents for immunotherapy-resistant cancers. SIGNIFICANCE: To enhance the effectiveness of immunotherapies in resistant or nonresponsive cancers, it is important to develop inhibitors of enzymes that negatively influence the outcome of treatments. We have designed and evaluated small-molecule inhibitors of PTPN2 demonstrating that these compounds may have clinical utility as sensitizing agents for immunotherapy-resistant cancers. American Association for Cancer Research 2023-01-24 /pmc/articles/PMC10035454/ /pubmed/36968224 http://dx.doi.org/10.1158/2767-9764.CRC-21-0186 Text en © 2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
spellingShingle Research Article
Zhu, Zhouting
Tang, Rachel
Huff, Sarah
Kummetha, Indrasena Reddy
Wang, Lingling
Li, Na
Rana, Tariq M.
Small-molecule PTPN2 Inhibitors Sensitize Resistant Melanoma to Anti-PD-1 Immunotherapy
title Small-molecule PTPN2 Inhibitors Sensitize Resistant Melanoma to Anti-PD-1 Immunotherapy
title_full Small-molecule PTPN2 Inhibitors Sensitize Resistant Melanoma to Anti-PD-1 Immunotherapy
title_fullStr Small-molecule PTPN2 Inhibitors Sensitize Resistant Melanoma to Anti-PD-1 Immunotherapy
title_full_unstemmed Small-molecule PTPN2 Inhibitors Sensitize Resistant Melanoma to Anti-PD-1 Immunotherapy
title_short Small-molecule PTPN2 Inhibitors Sensitize Resistant Melanoma to Anti-PD-1 Immunotherapy
title_sort small-molecule ptpn2 inhibitors sensitize resistant melanoma to anti-pd-1 immunotherapy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035454/
https://www.ncbi.nlm.nih.gov/pubmed/36968224
http://dx.doi.org/10.1158/2767-9764.CRC-21-0186
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