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.

Automated summary

Immune checkpoint inhibitors (ICIs) are a revolutionary cancer treatment with mechanisms not fully understood. This study investigates the role of the enzyme carbonic anhydrase IX (CAIX) in ICI success using an in silico model of the tumor microenvironment. The model shows that CAIX-expressing tumors acidify their environment, reducing immune infiltration and increasing tumor burden. Additionally, suppressing CAIX improves the response to anti-PD-1 treatment, independent of PD-L1 expression.