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Radiation Augments the Local Anti-Tumor Effect of In Situ Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models

INTRODUCTION: Combining CpG oligodeoxynucleotides with anti-OX40 agonist antibody (CpG+OX40) is able to generate an effective in situ vaccine in some tumor models, including the A20 lymphoma model. Immunologically “cold” tumors, which are typically less responsive to immunotherapy, are characterized...

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Autores principales: Pieper, Alexander A., Zangl, Luke M., Speigelman, Dan V., Feils, Arika S., Hoefges, Anna, Jagodinsky, Justin C., Felder, Mildred A., Tsarovsky, Noah W., Arthur, Ian S., Brown, Ryan J., Birstler, Jen, Le, Trang, Carlson, Peter M., Bates, Amber M., Hank, Jacquelyn A., Rakhmilevich, Alexander L., Erbe, Amy K., Sondel, Paul M., Patel, Ravi B., Morris, Zachary S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634717/
https://www.ncbi.nlm.nih.gov/pubmed/34868010
http://dx.doi.org/10.3389/fimmu.2021.763888
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author Pieper, Alexander A.
Zangl, Luke M.
Speigelman, Dan V.
Feils, Arika S.
Hoefges, Anna
Jagodinsky, Justin C.
Felder, Mildred A.
Tsarovsky, Noah W.
Arthur, Ian S.
Brown, Ryan J.
Birstler, Jen
Le, Trang
Carlson, Peter M.
Bates, Amber M.
Hank, Jacquelyn A.
Rakhmilevich, Alexander L.
Erbe, Amy K.
Sondel, Paul M.
Patel, Ravi B.
Morris, Zachary S.
author_facet Pieper, Alexander A.
Zangl, Luke M.
Speigelman, Dan V.
Feils, Arika S.
Hoefges, Anna
Jagodinsky, Justin C.
Felder, Mildred A.
Tsarovsky, Noah W.
Arthur, Ian S.
Brown, Ryan J.
Birstler, Jen
Le, Trang
Carlson, Peter M.
Bates, Amber M.
Hank, Jacquelyn A.
Rakhmilevich, Alexander L.
Erbe, Amy K.
Sondel, Paul M.
Patel, Ravi B.
Morris, Zachary S.
author_sort Pieper, Alexander A.
collection PubMed
description INTRODUCTION: Combining CpG oligodeoxynucleotides with anti-OX40 agonist antibody (CpG+OX40) is able to generate an effective in situ vaccine in some tumor models, including the A20 lymphoma model. Immunologically “cold” tumors, which are typically less responsive to immunotherapy, are characterized by few tumor infiltrating lymphocytes (TILs), low mutation burden, and limited neoantigen expression. Radiation therapy (RT) can change the tumor microenvironment (TME) of an immunologically “cold” tumor. This study investigated the effect of combining RT with the in situ vaccine CpG+OX40 in immunologically “cold” tumor models. METHODS: Mice bearing flank tumors (A20 lymphoma, B78 melanoma or 4T1 breast cancer) were treated with combinations of local RT, CpG, and/or OX40, and response to treatment was monitored. Flow cytometry and quantitative polymerase chain reaction (qPCR) experiments were conducted to study differences in the TME, secondary lymphoid organs, and immune activation after treatment. RESULTS: An in situ vaccine regimen of CpG+OX40, which was effective in the A20 model, did not significantly improve tumor response or survival in the “cold” B78 and 4T1 models, as tested here. In both models, treatment with RT prior to CpG+OX40 enabled a local response to this in situ vaccine, significantly improving the anti-tumor response and survival compared to RT alone or CpG+OX40 alone. RT increased OX40 expression on tumor infiltrating CD4+ non-regulatory T cells. RT+CpG+OX40 increased the ratio of tumor-infiltrating effector T cells to T regulatory cells and significantly increased CD4+ and CD8+ T cell activation in the tumor draining lymph node (TDLN) and spleen. CONCLUSION: RT significantly improves the local anti-tumor effect of the in situ vaccine CpG+OX40 in immunologically “cold”, solid, murine tumor models where RT or CpG+OX40 alone fail to stimulate tumor regression.
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spelling pubmed-86347172021-12-02 Radiation Augments the Local Anti-Tumor Effect of In Situ Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models Pieper, Alexander A. Zangl, Luke M. Speigelman, Dan V. Feils, Arika S. Hoefges, Anna Jagodinsky, Justin C. Felder, Mildred A. Tsarovsky, Noah W. Arthur, Ian S. Brown, Ryan J. Birstler, Jen Le, Trang Carlson, Peter M. Bates, Amber M. Hank, Jacquelyn A. Rakhmilevich, Alexander L. Erbe, Amy K. Sondel, Paul M. Patel, Ravi B. Morris, Zachary S. Front Immunol Immunology INTRODUCTION: Combining CpG oligodeoxynucleotides with anti-OX40 agonist antibody (CpG+OX40) is able to generate an effective in situ vaccine in some tumor models, including the A20 lymphoma model. Immunologically “cold” tumors, which are typically less responsive to immunotherapy, are characterized by few tumor infiltrating lymphocytes (TILs), low mutation burden, and limited neoantigen expression. Radiation therapy (RT) can change the tumor microenvironment (TME) of an immunologically “cold” tumor. This study investigated the effect of combining RT with the in situ vaccine CpG+OX40 in immunologically “cold” tumor models. METHODS: Mice bearing flank tumors (A20 lymphoma, B78 melanoma or 4T1 breast cancer) were treated with combinations of local RT, CpG, and/or OX40, and response to treatment was monitored. Flow cytometry and quantitative polymerase chain reaction (qPCR) experiments were conducted to study differences in the TME, secondary lymphoid organs, and immune activation after treatment. RESULTS: An in situ vaccine regimen of CpG+OX40, which was effective in the A20 model, did not significantly improve tumor response or survival in the “cold” B78 and 4T1 models, as tested here. In both models, treatment with RT prior to CpG+OX40 enabled a local response to this in situ vaccine, significantly improving the anti-tumor response and survival compared to RT alone or CpG+OX40 alone. RT increased OX40 expression on tumor infiltrating CD4+ non-regulatory T cells. RT+CpG+OX40 increased the ratio of tumor-infiltrating effector T cells to T regulatory cells and significantly increased CD4+ and CD8+ T cell activation in the tumor draining lymph node (TDLN) and spleen. CONCLUSION: RT significantly improves the local anti-tumor effect of the in situ vaccine CpG+OX40 in immunologically “cold”, solid, murine tumor models where RT or CpG+OX40 alone fail to stimulate tumor regression. Frontiers Media S.A. 2021-11-15 /pmc/articles/PMC8634717/ /pubmed/34868010 http://dx.doi.org/10.3389/fimmu.2021.763888 Text en Copyright © 2021 Pieper, Zangl, Speigelman, Feils, Hoefges, Jagodinsky, Felder, Tsarovsky, Arthur, Brown, Birstler, Le, Carlson, Bates, Hank, Rakhmilevich, Erbe, Sondel, Patel and Morris 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
Pieper, Alexander A.
Zangl, Luke M.
Speigelman, Dan V.
Feils, Arika S.
Hoefges, Anna
Jagodinsky, Justin C.
Felder, Mildred A.
Tsarovsky, Noah W.
Arthur, Ian S.
Brown, Ryan J.
Birstler, Jen
Le, Trang
Carlson, Peter M.
Bates, Amber M.
Hank, Jacquelyn A.
Rakhmilevich, Alexander L.
Erbe, Amy K.
Sondel, Paul M.
Patel, Ravi B.
Morris, Zachary S.
Radiation Augments the Local Anti-Tumor Effect of In Situ Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models
title Radiation Augments the Local Anti-Tumor Effect of In Situ Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models
title_full Radiation Augments the Local Anti-Tumor Effect of In Situ Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models
title_fullStr Radiation Augments the Local Anti-Tumor Effect of In Situ Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models
title_full_unstemmed Radiation Augments the Local Anti-Tumor Effect of In Situ Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models
title_short Radiation Augments the Local Anti-Tumor Effect of In Situ Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models
title_sort radiation augments the local anti-tumor effect of in situ vaccine with cpg-oligodeoxynucleotides and anti-ox40 in immunologically cold tumor models
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634717/
https://www.ncbi.nlm.nih.gov/pubmed/34868010
http://dx.doi.org/10.3389/fimmu.2021.763888
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