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Quantifying the impact of immunotherapy on RNA dynamics in cancer

BACKGROUND: Checkpoint inhibitor (CPI) immunotherapies have provided durable clinical responses across a range of solid tumor types for some patients with cancer. Nonetheless, response rates to CPI vary greatly between cancer types. Resolving intratumor transcriptomic changes induced by CPI may impr...

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Autores principales: Usaite, Ieva, Biswas, Dhruva, Dijkstra, Krijn, Watkins, Thomas BK, Pich, Oriol, Puttick, Clare, Angelova, Mihaela, Thakkar, Krupa, Hiley, Crispin, Birkbak, Nicolai, Kok, Marleen, Zaccaria, Simone, Wu, Yin, Litchfield, Kevin, Swanton, Charles, Kanu, Nnennaya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10626770/
https://www.ncbi.nlm.nih.gov/pubmed/37914385
http://dx.doi.org/10.1136/jitc-2023-007870
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author Usaite, Ieva
Biswas, Dhruva
Dijkstra, Krijn
Watkins, Thomas BK
Pich, Oriol
Puttick, Clare
Angelova, Mihaela
Thakkar, Krupa
Hiley, Crispin
Birkbak, Nicolai
Kok, Marleen
Zaccaria, Simone
Wu, Yin
Litchfield, Kevin
Swanton, Charles
Kanu, Nnennaya
author_facet Usaite, Ieva
Biswas, Dhruva
Dijkstra, Krijn
Watkins, Thomas BK
Pich, Oriol
Puttick, Clare
Angelova, Mihaela
Thakkar, Krupa
Hiley, Crispin
Birkbak, Nicolai
Kok, Marleen
Zaccaria, Simone
Wu, Yin
Litchfield, Kevin
Swanton, Charles
Kanu, Nnennaya
author_sort Usaite, Ieva
collection PubMed
description BACKGROUND: Checkpoint inhibitor (CPI) immunotherapies have provided durable clinical responses across a range of solid tumor types for some patients with cancer. Nonetheless, response rates to CPI vary greatly between cancer types. Resolving intratumor transcriptomic changes induced by CPI may improve our understanding of the mechanisms of sensitivity and resistance. METHODS: We assembled a cohort of longitudinal pre-therapy and on-therapy samples from 174 patients treated with CPI across six cancer types by leveraging transcriptomic sequencing data from five studies. RESULTS: Meta-analyses of published RNA markers revealed an on-therapy pattern of immune reinvigoration in patients with breast cancer, which was not discernible pre-therapy, providing biological insight into the impact of CPI on the breast cancer immune microenvironment. We identified 98 breast cancer-specific correlates of CPI response, including 13 genes which are known IO targets, such as toll-like receptors TLR1, TLR4, and TLR8, that could hold potential as combination targets for patients with breast cancer receiving CPI treatment. Furthermore, we demonstrate that a subset of response genes identified in breast cancer are already highly expressed pre-therapy in melanoma, and additionally we establish divergent RNA dynamics between breast cancer and melanoma following CPI treatment, which may suggest distinct immune microenvironments between the two cancer types. CONCLUSIONS: Overall, delineating longitudinal RNA dynamics following CPI therapy sheds light on the mechanisms underlying diverging response trajectories, and identifies putative targets for combination therapy.
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spelling pubmed-106267702023-11-07 Quantifying the impact of immunotherapy on RNA dynamics in cancer Usaite, Ieva Biswas, Dhruva Dijkstra, Krijn Watkins, Thomas BK Pich, Oriol Puttick, Clare Angelova, Mihaela Thakkar, Krupa Hiley, Crispin Birkbak, Nicolai Kok, Marleen Zaccaria, Simone Wu, Yin Litchfield, Kevin Swanton, Charles Kanu, Nnennaya J Immunother Cancer Basic Tumor Immunology BACKGROUND: Checkpoint inhibitor (CPI) immunotherapies have provided durable clinical responses across a range of solid tumor types for some patients with cancer. Nonetheless, response rates to CPI vary greatly between cancer types. Resolving intratumor transcriptomic changes induced by CPI may improve our understanding of the mechanisms of sensitivity and resistance. METHODS: We assembled a cohort of longitudinal pre-therapy and on-therapy samples from 174 patients treated with CPI across six cancer types by leveraging transcriptomic sequencing data from five studies. RESULTS: Meta-analyses of published RNA markers revealed an on-therapy pattern of immune reinvigoration in patients with breast cancer, which was not discernible pre-therapy, providing biological insight into the impact of CPI on the breast cancer immune microenvironment. We identified 98 breast cancer-specific correlates of CPI response, including 13 genes which are known IO targets, such as toll-like receptors TLR1, TLR4, and TLR8, that could hold potential as combination targets for patients with breast cancer receiving CPI treatment. Furthermore, we demonstrate that a subset of response genes identified in breast cancer are already highly expressed pre-therapy in melanoma, and additionally we establish divergent RNA dynamics between breast cancer and melanoma following CPI treatment, which may suggest distinct immune microenvironments between the two cancer types. CONCLUSIONS: Overall, delineating longitudinal RNA dynamics following CPI therapy sheds light on the mechanisms underlying diverging response trajectories, and identifies putative targets for combination therapy. BMJ Publishing Group 2023-11-01 /pmc/articles/PMC10626770/ /pubmed/37914385 http://dx.doi.org/10.1136/jitc-2023-007870 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Basic Tumor Immunology
Usaite, Ieva
Biswas, Dhruva
Dijkstra, Krijn
Watkins, Thomas BK
Pich, Oriol
Puttick, Clare
Angelova, Mihaela
Thakkar, Krupa
Hiley, Crispin
Birkbak, Nicolai
Kok, Marleen
Zaccaria, Simone
Wu, Yin
Litchfield, Kevin
Swanton, Charles
Kanu, Nnennaya
Quantifying the impact of immunotherapy on RNA dynamics in cancer
title Quantifying the impact of immunotherapy on RNA dynamics in cancer
title_full Quantifying the impact of immunotherapy on RNA dynamics in cancer
title_fullStr Quantifying the impact of immunotherapy on RNA dynamics in cancer
title_full_unstemmed Quantifying the impact of immunotherapy on RNA dynamics in cancer
title_short Quantifying the impact of immunotherapy on RNA dynamics in cancer
title_sort quantifying the impact of immunotherapy on rna dynamics in cancer
topic Basic Tumor Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10626770/
https://www.ncbi.nlm.nih.gov/pubmed/37914385
http://dx.doi.org/10.1136/jitc-2023-007870
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