An in silico model to study the impact of carbonic anhydrase IX expression on tumour growth and anti-PD-1 therapy
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Published on: April 6, 2016
Julia Grajek1, Jakob Nikolas Kather2, Jan Poleszczuk1
1Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Warsaw 02-109, Poland.
Abstract:
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.
Insights
Carbonic anhydrase IX (CAIX) in tumors creates an acidic environment, hindering immune cell infiltration and reducing cancer treatment effectiveness. Suppressing CAIX enhances anti-PD-1 therapy response, suggesting a promising combination strategy.
Area of Science:
- Oncology
- Immunology
- Computational Biology
Background:
- Immune checkpoint inhibitors (ICIs) are transforming cancer therapy, but their mechanisms require further elucidation.
- The role of the pH-regulatory enzyme carbonic anhydrase IX (CAIX) in ICI efficacy remains unclear.
- Tumor microenvironment (TME) factors significantly influence treatment outcomes.
Purpose of the Study:
- To investigate the impact of carbonic anhydrase IX (CAIX) on the efficacy of immune checkpoint inhibitors (ICIs).
- To develop and utilize an in silico model of the tumor microenvironment to simulate TME dynamics and treatment responses.
- To explore the potential of combining CAIX inhibition with anti-PD-1 therapy.
Main Methods:
- Development of a hybrid in silico model integrating an agent-based model of tumor-immune cell interactions with diffusion-reaction equations.
- Calibration of the model using existing literature data to analyze TME behavior.
- Simulation of CAIX expression and suppression effects on immune infiltration, tumor burden, and response to anti-PD-1 therapy.
Main Results:
- CAIX-expressing tumors acidified the TME, leading to a 90% reduction in immune infiltration and a 25% increase in tumor burden.
- Suppression of CAIX significantly improved the response to anti-PD-1 therapy, achieving 23% tumor reduction in CAIX knockouts versus 6% in CAIX-expressing tumors.
- The positive effect of CAIX suppression on anti-PD-1 response was observed independently of initial PD-L1 expression levels.
Conclusions:
- CAIX-expressing tumors create an immunosuppressive microenvironment that limits the effectiveness of ICIs.
- Combining ICIs with CAIX suppression presents a potentially effective therapeutic strategy, particularly for patients with CAIX-expressing tumors, irrespective of pre-treatment PD-L1 status.
- The developed in silico model can serve as a valuable high-throughput tool for predicting the efficacy of combinatorial cancer therapies.
