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Synergy of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC I–deficient and MHC I(+) tumors
Cyclic dinucleotides (CDN) and Toll-like receptor (TLR) ligands mobilize antitumor responses by natural killer (NK) cells and T cells, potentially serving as complementary therapies to immune checkpoint therapy. In the clinic thus far, however, CDN therapy targeting stimulator of interferon genes (S...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295797/ https://www.ncbi.nlm.nih.gov/pubmed/35588144 http://dx.doi.org/10.1073/pnas.2200568119 |
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author | Wolf, Natalie K. Blaj, Cristina Picton, Lora K. Snyder, Gail Zhang, Li Nicolai, Christopher J. Ndubaku, Chudi O. McWhirter, Sarah M. Garcia, K. Christopher Raulet, David H. |
author_facet | Wolf, Natalie K. Blaj, Cristina Picton, Lora K. Snyder, Gail Zhang, Li Nicolai, Christopher J. Ndubaku, Chudi O. McWhirter, Sarah M. Garcia, K. Christopher Raulet, David H. |
author_sort | Wolf, Natalie K. |
collection | PubMed |
description | Cyclic dinucleotides (CDN) and Toll-like receptor (TLR) ligands mobilize antitumor responses by natural killer (NK) cells and T cells, potentially serving as complementary therapies to immune checkpoint therapy. In the clinic thus far, however, CDN therapy targeting stimulator of interferon genes (STING) protein has yielded mixed results, perhaps because it initiates responses potently but does not provide signals to sustain activation and proliferation of activated cytotoxic lymphocytes. To improve efficacy, we combined CDN with a half life-extended interleukin-2 (IL-2) superkine, H9-MSA (mouse serum albumin). CDN/H9-MSA therapy induced dramatic long-term remissions of the most difficult to treat major histocompatibility complex class I (MHC I)–deficient and MHC I(+) tumor transplant models. H9-MSA combined with CpG oligonucleotide also induced potent responses. Mechanistically, tumor elimination required CD8 T cells and not NK cells in the case of MHC I(+) tumors and NK cells but not CD8 T cells in the case of MHC-deficient tumors. Furthermore, combination therapy resulted in more prolonged and more intense NK cell activation, cytotoxicity, and expression of cytotoxic effector molecules in comparison with monotherapy. Remarkably, in a primary autochthonous sarcoma model that is refractory to PD-1 checkpoint therapy, the combination of CDN/H9-MSA with checkpoint therapy yielded long-term remissions in the majority of the animals, mediated by T cells and NK cells. This combination therapy has the potential to activate responses in tumors resistant to current therapies and prevent MHC I loss accompanying acquired resistance of tumors to checkpoint therapy. |
format | Online Article Text |
id | pubmed-9295797 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-92957972022-07-20 Synergy of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC I–deficient and MHC I(+) tumors Wolf, Natalie K. Blaj, Cristina Picton, Lora K. Snyder, Gail Zhang, Li Nicolai, Christopher J. Ndubaku, Chudi O. McWhirter, Sarah M. Garcia, K. Christopher Raulet, David H. Proc Natl Acad Sci U S A Biological Sciences Cyclic dinucleotides (CDN) and Toll-like receptor (TLR) ligands mobilize antitumor responses by natural killer (NK) cells and T cells, potentially serving as complementary therapies to immune checkpoint therapy. In the clinic thus far, however, CDN therapy targeting stimulator of interferon genes (STING) protein has yielded mixed results, perhaps because it initiates responses potently but does not provide signals to sustain activation and proliferation of activated cytotoxic lymphocytes. To improve efficacy, we combined CDN with a half life-extended interleukin-2 (IL-2) superkine, H9-MSA (mouse serum albumin). CDN/H9-MSA therapy induced dramatic long-term remissions of the most difficult to treat major histocompatibility complex class I (MHC I)–deficient and MHC I(+) tumor transplant models. H9-MSA combined with CpG oligonucleotide also induced potent responses. Mechanistically, tumor elimination required CD8 T cells and not NK cells in the case of MHC I(+) tumors and NK cells but not CD8 T cells in the case of MHC-deficient tumors. Furthermore, combination therapy resulted in more prolonged and more intense NK cell activation, cytotoxicity, and expression of cytotoxic effector molecules in comparison with monotherapy. Remarkably, in a primary autochthonous sarcoma model that is refractory to PD-1 checkpoint therapy, the combination of CDN/H9-MSA with checkpoint therapy yielded long-term remissions in the majority of the animals, mediated by T cells and NK cells. This combination therapy has the potential to activate responses in tumors resistant to current therapies and prevent MHC I loss accompanying acquired resistance of tumors to checkpoint therapy. National Academy of Sciences 2022-05-19 2022-05-31 /pmc/articles/PMC9295797/ /pubmed/35588144 http://dx.doi.org/10.1073/pnas.2200568119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Wolf, Natalie K. Blaj, Cristina Picton, Lora K. Snyder, Gail Zhang, Li Nicolai, Christopher J. Ndubaku, Chudi O. McWhirter, Sarah M. Garcia, K. Christopher Raulet, David H. Synergy of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC I–deficient and MHC I(+) tumors |
title | Synergy of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC I–deficient and MHC I(+) tumors |
title_full | Synergy of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC I–deficient and MHC I(+) tumors |
title_fullStr | Synergy of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC I–deficient and MHC I(+) tumors |
title_full_unstemmed | Synergy of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC I–deficient and MHC I(+) tumors |
title_short | Synergy of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC I–deficient and MHC I(+) tumors |
title_sort | synergy of a sting agonist and an il-2 superkine in cancer immunotherapy against mhc i–deficient and mhc i(+) tumors |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295797/ https://www.ncbi.nlm.nih.gov/pubmed/35588144 http://dx.doi.org/10.1073/pnas.2200568119 |
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