An in silico model to study the impact of carbonic anhydrase IX expression on tumour growth and anti-PD-1 therapy
Immune checkpoint inhibitors (ICIs) are revolutionary cancer treatments. However, the mechanisms behind their effectiveness are not yet fully understood. Here, we aimed to investigate the role of the pH-regulatory enzyme carbonic anhydrase IX (CAIX) in ICI success. Consequently, we developed an in silico model of the tumour microenvironment. The hybrid model consists of an agent-based model of tumour-immune cell interactions, coupled with a set of diffusion-reaction equations describing substances in the environment. It is calibrated with data from the literature, enabling the study of its qualitative behaviour. In our model, CAIX-expressing tumours acidified their neighbourhood, thereby reducing immune infiltration by 90% (p < 0.001) and resulting in a 25% increase in tumour burden (p < 0.001). Moreover, suppression of CAIX improved the response to anti-PD-1 (23% tumour reduction in CAIX knockouts and 6% in CAIX-expressing tumours, p < 0.001), independently of initial PD-L1 expression. Our simulations suggest that patients with CAIX-expressing tumours could respond favourably to combining ICIs with CAIX suppression, even in the absence of pre-treatment PD-L1 expression. Furthermore, when calibrated with tumour-type-specific data, our model could serve as a high-throughput tool for testing the effectiveness of such a combinatorial approach.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
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| Enthalten in: |
Journal of the Royal Society, Interface - 20(2023), 198 vom: 01. Jan., Seite 20220654 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Grajek, Julia [VerfasserIn] |
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| Links: |
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| Themen: |
Agent-based model |
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| Anmerkungen: |
Date Completed 26.01.2023 Date Revised 26.01.2024 published: Print-Electronic figshare: 10.6084/m9.figshare.c.6384994 Citation Status MEDLINE |
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| doi: |
10.1098/rsif.2022.0654 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35205686X |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Immune checkpoint inhibitors (ICIs) are revolutionary cancer treatments. However, the mechanisms behind their effectiveness are not yet fully understood. Here, we aimed to investigate the role of the pH-regulatory enzyme carbonic anhydrase IX (CAIX) in ICI success. Consequently, we developed an in silico model of the tumour microenvironment. The hybrid model consists of an agent-based model of tumour-immune cell interactions, coupled with a set of diffusion-reaction equations describing substances in the environment. It is calibrated with data from the literature, enabling the study of its qualitative behaviour. In our model, CAIX-expressing tumours acidified their neighbourhood, thereby reducing immune infiltration by 90% (p < 0.001) and resulting in a 25% increase in tumour burden (p < 0.001). Moreover, suppression of CAIX improved the response to anti-PD-1 (23% tumour reduction in CAIX knockouts and 6% in CAIX-expressing tumours, p < 0.001), independently of initial PD-L1 expression. Our simulations suggest that patients with CAIX-expressing tumours could respond favourably to combining ICIs with CAIX suppression, even in the absence of pre-treatment PD-L1 expression. Furthermore, when calibrated with tumour-type-specific data, our model could serve as a high-throughput tool for testing the effectiveness of such a combinatorial approach | ||
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| 700 | 1 | |a Poleszczuk, Jan |e verfasserin |4 aut | |
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