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Oncolytic adenovirus decreases the proportion of TIM-3(+) subset of tumor-infiltrating CD8(+) T cells with correlation to improved survival in patients with cancer
BACKGROUND: Oncolytic viruses are a potent form of active immunotherapy, capable of invoking antitumor T-cell responses. Meanwhile, less is known about their effects on immune checkpoints, the main targets for passive immunotherapy of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3) is a coi...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8867324/ https://www.ncbi.nlm.nih.gov/pubmed/35193929 http://dx.doi.org/10.1136/jitc-2021-003490 |
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author | Liikanen, Ilkka Basnet, Saru Quixabeira, Dafne C A Taipale, Kristian Hemminki, Otto Oksanen, Minna Kankainen, Matti Juhila, Juuso Kanerva, Anna Joensuu, Timo Tähtinen, Siri Hemminki, Akseli |
author_facet | Liikanen, Ilkka Basnet, Saru Quixabeira, Dafne C A Taipale, Kristian Hemminki, Otto Oksanen, Minna Kankainen, Matti Juhila, Juuso Kanerva, Anna Joensuu, Timo Tähtinen, Siri Hemminki, Akseli |
author_sort | Liikanen, Ilkka |
collection | PubMed |
description | BACKGROUND: Oncolytic viruses are a potent form of active immunotherapy, capable of invoking antitumor T-cell responses. Meanwhile, less is known about their effects on immune checkpoints, the main targets for passive immunotherapy of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3) is a coinhibitory checkpoint driving T-cell exhaustion in cancer. Here we investigated the effects of oncolytic adenovirus on the TIM-3 checkpoint on tumor-infiltrating immune cells and clinical impact in patients with cancer receiving oncolytic immunotherapy. METHODS: Modulation of TIM-3 expression on tumor-infiltrating immune cells was studied preclinically in B16 melanoma following intratumoral treatment with Ad5/3∆24-granulocyte-macrophage colony-stimulating factor oncolytic adenovirus. We conducted a retrospective longitudinal analysis of 15 patients with advanced-stage cancer with tumor-site biopsies before and after oncolytic immunotherapy, treated in the Advanced Therapy Access Program (ISRCTN10141600, April 5, 2011). Following patient stratification with regard to TIM-3 (increase vs decrease in tumors), overall survival and imaging/marker responses were evaluated by log-rank and Fisher’s test, while coinhibitory receptors/ligands, transcriptomic changes and tumor-reactive and tumor-infltrating immune cells in biopsies and blood samples were studied by microarray rank-based statistics and immunoassays. RESULTS: Preclinically, TIM-3(+) tumor-infiltrating lymphocytes (TILs) in B16 melanoma showed an exhausted phenotype, whereas oncolytic adenovirus treatment significantly reduced the proportion of TIM-3(+) TIL subset through recruitment of less-exhausted CD8(+) TIL. Decrease of TIM-3 was observed in 60% of patients, which was associated with improved overall survival over TIM-3 increase patients (p=0.004), together with evidence of clinical benefit by imaging and blood analyses. Coinhibitory T-cell receptors and ligands were consistently associated with TIM-3 changes in gene expression data, while core transcriptional exhaustion programs and T-cell dysfunction were enriched in patients with TIM-3 increase, thus identifying patients potentially benefiting from checkpoint blockade. In striking contrast, patients with TIM-3 decrease displayed an acute inflammatory signature, redistribution of tumor-reactive CD8(+) lymphocytes and higher influx of CD8(+) TIL into tumors, which were associated with the longest overall survival, suggesting benefit from active immunotherapy. CONCLUSIONS: Our results indicate a key role for the TIM-3 immune checkpoint in oncolytic adenoviral immunotherapy. Moreover, our results identify TIM-3 as a potential biomarker for oncolytic adenoviruses and create rationale for combination with passive immunotherapy for a subset of patients. |
format | Online Article Text |
id | pubmed-8867324 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-88673242022-03-15 Oncolytic adenovirus decreases the proportion of TIM-3(+) subset of tumor-infiltrating CD8(+) T cells with correlation to improved survival in patients with cancer Liikanen, Ilkka Basnet, Saru Quixabeira, Dafne C A Taipale, Kristian Hemminki, Otto Oksanen, Minna Kankainen, Matti Juhila, Juuso Kanerva, Anna Joensuu, Timo Tähtinen, Siri Hemminki, Akseli J Immunother Cancer Oncolytic and Local Immunotherapy BACKGROUND: Oncolytic viruses are a potent form of active immunotherapy, capable of invoking antitumor T-cell responses. Meanwhile, less is known about their effects on immune checkpoints, the main targets for passive immunotherapy of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3) is a coinhibitory checkpoint driving T-cell exhaustion in cancer. Here we investigated the effects of oncolytic adenovirus on the TIM-3 checkpoint on tumor-infiltrating immune cells and clinical impact in patients with cancer receiving oncolytic immunotherapy. METHODS: Modulation of TIM-3 expression on tumor-infiltrating immune cells was studied preclinically in B16 melanoma following intratumoral treatment with Ad5/3∆24-granulocyte-macrophage colony-stimulating factor oncolytic adenovirus. We conducted a retrospective longitudinal analysis of 15 patients with advanced-stage cancer with tumor-site biopsies before and after oncolytic immunotherapy, treated in the Advanced Therapy Access Program (ISRCTN10141600, April 5, 2011). Following patient stratification with regard to TIM-3 (increase vs decrease in tumors), overall survival and imaging/marker responses were evaluated by log-rank and Fisher’s test, while coinhibitory receptors/ligands, transcriptomic changes and tumor-reactive and tumor-infltrating immune cells in biopsies and blood samples were studied by microarray rank-based statistics and immunoassays. RESULTS: Preclinically, TIM-3(+) tumor-infiltrating lymphocytes (TILs) in B16 melanoma showed an exhausted phenotype, whereas oncolytic adenovirus treatment significantly reduced the proportion of TIM-3(+) TIL subset through recruitment of less-exhausted CD8(+) TIL. Decrease of TIM-3 was observed in 60% of patients, which was associated with improved overall survival over TIM-3 increase patients (p=0.004), together with evidence of clinical benefit by imaging and blood analyses. Coinhibitory T-cell receptors and ligands were consistently associated with TIM-3 changes in gene expression data, while core transcriptional exhaustion programs and T-cell dysfunction were enriched in patients with TIM-3 increase, thus identifying patients potentially benefiting from checkpoint blockade. In striking contrast, patients with TIM-3 decrease displayed an acute inflammatory signature, redistribution of tumor-reactive CD8(+) lymphocytes and higher influx of CD8(+) TIL into tumors, which were associated with the longest overall survival, suggesting benefit from active immunotherapy. CONCLUSIONS: Our results indicate a key role for the TIM-3 immune checkpoint in oncolytic adenoviral immunotherapy. Moreover, our results identify TIM-3 as a potential biomarker for oncolytic adenoviruses and create rationale for combination with passive immunotherapy for a subset of patients. BMJ Publishing Group 2022-02-22 /pmc/articles/PMC8867324/ /pubmed/35193929 http://dx.doi.org/10.1136/jitc-2021-003490 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Oncolytic and Local Immunotherapy Liikanen, Ilkka Basnet, Saru Quixabeira, Dafne C A Taipale, Kristian Hemminki, Otto Oksanen, Minna Kankainen, Matti Juhila, Juuso Kanerva, Anna Joensuu, Timo Tähtinen, Siri Hemminki, Akseli Oncolytic adenovirus decreases the proportion of TIM-3(+) subset of tumor-infiltrating CD8(+) T cells with correlation to improved survival in patients with cancer |
title | Oncolytic adenovirus decreases the proportion of TIM-3(+) subset of tumor-infiltrating CD8(+) T cells with correlation to improved survival in patients with cancer |
title_full | Oncolytic adenovirus decreases the proportion of TIM-3(+) subset of tumor-infiltrating CD8(+) T cells with correlation to improved survival in patients with cancer |
title_fullStr | Oncolytic adenovirus decreases the proportion of TIM-3(+) subset of tumor-infiltrating CD8(+) T cells with correlation to improved survival in patients with cancer |
title_full_unstemmed | Oncolytic adenovirus decreases the proportion of TIM-3(+) subset of tumor-infiltrating CD8(+) T cells with correlation to improved survival in patients with cancer |
title_short | Oncolytic adenovirus decreases the proportion of TIM-3(+) subset of tumor-infiltrating CD8(+) T cells with correlation to improved survival in patients with cancer |
title_sort | oncolytic adenovirus decreases the proportion of tim-3(+) subset of tumor-infiltrating cd8(+) t cells with correlation to improved survival in patients with cancer |
topic | Oncolytic and Local Immunotherapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8867324/ https://www.ncbi.nlm.nih.gov/pubmed/35193929 http://dx.doi.org/10.1136/jitc-2021-003490 |
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