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Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer

Immune checkpoint inhibitors(1) result in impressive clinical responses(2–5) but optimal results will require combination with each other(6) and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here, we report major tumor regressions in a subset o...

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Autores principales: Victor, Christina Twyman-Saint, Rech, Andrew J., Maity, Amit, Rengan, Ramesh, Pauken, Kristen E., Stelekati, Erietta, Benci, Joseph L., Xu, Bihui, Dada, Hannah, Odorizzi, Pamela M., Herati, Ramin S., Mansfield, Kathleen D., Patsch, Dana, Amaravadi, Ravi K., Schuchter, Lynn M., Ishwaran, Hemant, Mick, Rosemarie, Pryma, Daniel A., Xu, Xiaowei, Feldman, Michael D., Gangadhar, Tara C., Hahn, Stephen M., Wherry, E. John, Vonderheide, Robert H., Minn, Andy J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401634/
https://www.ncbi.nlm.nih.gov/pubmed/25754329
http://dx.doi.org/10.1038/nature14292
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author Victor, Christina Twyman-Saint
Rech, Andrew J.
Maity, Amit
Rengan, Ramesh
Pauken, Kristen E.
Stelekati, Erietta
Benci, Joseph L.
Xu, Bihui
Dada, Hannah
Odorizzi, Pamela M.
Herati, Ramin S.
Mansfield, Kathleen D.
Patsch, Dana
Amaravadi, Ravi K.
Schuchter, Lynn M.
Ishwaran, Hemant
Mick, Rosemarie
Pryma, Daniel A.
Xu, Xiaowei
Feldman, Michael D.
Gangadhar, Tara C.
Hahn, Stephen M.
Wherry, E. John
Vonderheide, Robert H.
Minn, Andy J.
author_facet Victor, Christina Twyman-Saint
Rech, Andrew J.
Maity, Amit
Rengan, Ramesh
Pauken, Kristen E.
Stelekati, Erietta
Benci, Joseph L.
Xu, Bihui
Dada, Hannah
Odorizzi, Pamela M.
Herati, Ramin S.
Mansfield, Kathleen D.
Patsch, Dana
Amaravadi, Ravi K.
Schuchter, Lynn M.
Ishwaran, Hemant
Mick, Rosemarie
Pryma, Daniel A.
Xu, Xiaowei
Feldman, Michael D.
Gangadhar, Tara C.
Hahn, Stephen M.
Wherry, E. John
Vonderheide, Robert H.
Minn, Andy J.
author_sort Victor, Christina Twyman-Saint
collection PubMed
description Immune checkpoint inhibitors(1) result in impressive clinical responses(2–5) but optimal results will require combination with each other(6) and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here, we report major tumor regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation (RT) and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires RT, anti-CTLA4, and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T regulatory cells (Tregs) to increase the CD8 T cell to Treg (CD8/Treg) ratio. RT enhances the diversity of the T cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while RT shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligo-clonal T cell expansion. Similar to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumors to escape anti-CTLA4-based therapy, and the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response and immunity through distinct mechanisms.
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spelling pubmed-44016342015-10-16 Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer Victor, Christina Twyman-Saint Rech, Andrew J. Maity, Amit Rengan, Ramesh Pauken, Kristen E. Stelekati, Erietta Benci, Joseph L. Xu, Bihui Dada, Hannah Odorizzi, Pamela M. Herati, Ramin S. Mansfield, Kathleen D. Patsch, Dana Amaravadi, Ravi K. Schuchter, Lynn M. Ishwaran, Hemant Mick, Rosemarie Pryma, Daniel A. Xu, Xiaowei Feldman, Michael D. Gangadhar, Tara C. Hahn, Stephen M. Wherry, E. John Vonderheide, Robert H. Minn, Andy J. Nature Article Immune checkpoint inhibitors(1) result in impressive clinical responses(2–5) but optimal results will require combination with each other(6) and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here, we report major tumor regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation (RT) and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires RT, anti-CTLA4, and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T regulatory cells (Tregs) to increase the CD8 T cell to Treg (CD8/Treg) ratio. RT enhances the diversity of the T cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while RT shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligo-clonal T cell expansion. Similar to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumors to escape anti-CTLA4-based therapy, and the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response and immunity through distinct mechanisms. 2015-03-09 2015-04-16 /pmc/articles/PMC4401634/ /pubmed/25754329 http://dx.doi.org/10.1038/nature14292 Text en Reprints and permissions information is available at www.nature.com/reprints
spellingShingle Article
Victor, Christina Twyman-Saint
Rech, Andrew J.
Maity, Amit
Rengan, Ramesh
Pauken, Kristen E.
Stelekati, Erietta
Benci, Joseph L.
Xu, Bihui
Dada, Hannah
Odorizzi, Pamela M.
Herati, Ramin S.
Mansfield, Kathleen D.
Patsch, Dana
Amaravadi, Ravi K.
Schuchter, Lynn M.
Ishwaran, Hemant
Mick, Rosemarie
Pryma, Daniel A.
Xu, Xiaowei
Feldman, Michael D.
Gangadhar, Tara C.
Hahn, Stephen M.
Wherry, E. John
Vonderheide, Robert H.
Minn, Andy J.
Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer
title Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer
title_full Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer
title_fullStr Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer
title_full_unstemmed Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer
title_short Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer
title_sort radiation and dual checkpoint blockade activates non-redundant immune mechanisms in cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401634/
https://www.ncbi.nlm.nih.gov/pubmed/25754329
http://dx.doi.org/10.1038/nature14292
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