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Carbonic Anhydrase IX Suppression Shifts Partial Response to Checkpoint Inhibitors into Complete Tumor Eradication: Model-Based Investigation

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of solid malignancies, including non-small-cell lung cancer. However, immunotherapy resistance constitutes a significant challenge. To investigate carbonic anhydrase IX (CAIX) as a driver of resistance, we built a differential equ...

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Detalles Bibliográficos
Autores principales: Grajek, Julia, Poleszczuk, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10298206/
https://www.ncbi.nlm.nih.gov/pubmed/37373220
http://dx.doi.org/10.3390/ijms241210068
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author Grajek, Julia
Poleszczuk, Jan
author_facet Grajek, Julia
Poleszczuk, Jan
author_sort Grajek, Julia
collection PubMed
description Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of solid malignancies, including non-small-cell lung cancer. However, immunotherapy resistance constitutes a significant challenge. To investigate carbonic anhydrase IX (CAIX) as a driver of resistance, we built a differential equation model of tumor–immune interactions. The model considers treatment with the small molecule CAIX inhibitor SLC-0111 in combination with ICIs. Numerical simulations showed that, given an efficient immune response, CAIX KO tumors tended toward tumor elimination in contrast to their CAIX-expressing counterparts, which stabilized close to the positive equilibrium. Importantly, we demonstrated that short-term combination therapy with a CAIX inhibitor and immunotherapy could shift the asymptotic behavior of the original model from stable disease to tumor eradication. Finally, we calibrated the model with data from murine experiments on CAIX suppression and combination therapy with anti-PD-1 and anti-CTLA-4. Concluding, we have developed a model that reproduces experimental findings and enables the investigation of combination therapies. Our model suggests that transient CAIX inhibition may induce tumor regression, given a sufficient immune infiltrate in the tumor, which can be boosted with ICIs.
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spelling pubmed-102982062023-06-28 Carbonic Anhydrase IX Suppression Shifts Partial Response to Checkpoint Inhibitors into Complete Tumor Eradication: Model-Based Investigation Grajek, Julia Poleszczuk, Jan Int J Mol Sci Article Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of solid malignancies, including non-small-cell lung cancer. However, immunotherapy resistance constitutes a significant challenge. To investigate carbonic anhydrase IX (CAIX) as a driver of resistance, we built a differential equation model of tumor–immune interactions. The model considers treatment with the small molecule CAIX inhibitor SLC-0111 in combination with ICIs. Numerical simulations showed that, given an efficient immune response, CAIX KO tumors tended toward tumor elimination in contrast to their CAIX-expressing counterparts, which stabilized close to the positive equilibrium. Importantly, we demonstrated that short-term combination therapy with a CAIX inhibitor and immunotherapy could shift the asymptotic behavior of the original model from stable disease to tumor eradication. Finally, we calibrated the model with data from murine experiments on CAIX suppression and combination therapy with anti-PD-1 and anti-CTLA-4. Concluding, we have developed a model that reproduces experimental findings and enables the investigation of combination therapies. Our model suggests that transient CAIX inhibition may induce tumor regression, given a sufficient immune infiltrate in the tumor, which can be boosted with ICIs. MDPI 2023-06-13 /pmc/articles/PMC10298206/ /pubmed/37373220 http://dx.doi.org/10.3390/ijms241210068 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Grajek, Julia
Poleszczuk, Jan
Carbonic Anhydrase IX Suppression Shifts Partial Response to Checkpoint Inhibitors into Complete Tumor Eradication: Model-Based Investigation
title Carbonic Anhydrase IX Suppression Shifts Partial Response to Checkpoint Inhibitors into Complete Tumor Eradication: Model-Based Investigation
title_full Carbonic Anhydrase IX Suppression Shifts Partial Response to Checkpoint Inhibitors into Complete Tumor Eradication: Model-Based Investigation
title_fullStr Carbonic Anhydrase IX Suppression Shifts Partial Response to Checkpoint Inhibitors into Complete Tumor Eradication: Model-Based Investigation
title_full_unstemmed Carbonic Anhydrase IX Suppression Shifts Partial Response to Checkpoint Inhibitors into Complete Tumor Eradication: Model-Based Investigation
title_short Carbonic Anhydrase IX Suppression Shifts Partial Response to Checkpoint Inhibitors into Complete Tumor Eradication: Model-Based Investigation
title_sort carbonic anhydrase ix suppression shifts partial response to checkpoint inhibitors into complete tumor eradication: model-based investigation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10298206/
https://www.ncbi.nlm.nih.gov/pubmed/37373220
http://dx.doi.org/10.3390/ijms241210068
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