Mathematical modeling identifies LAG3 and HAVCR2 as biomarkers of T cell exhaustion in melanoma

Cytotoxic T lymphocytes (CTLs) control tumors via lysis of antigen-presenting tar-gets or through secretion of cytokines such as interferon -g (IFNG), which inhibit tumor cell proliferation. Improved understanding of CTL interactions within solid tumors will aid the development of immunotherapeutic strategies against cancer. In this study, we take a systems biology approach to compare the importance of cytolytic versus IFNG-mediated cytostatic effects in a murine melanoma model (B16F10) and to dissect the contribution of immune checkpoints HAVCR2, LAG3, and PDCD1/CD274 to CTL exhaustion. We integrated multimodal data to inform an ordinary differential equation (ODE) model of CTL activities inside the tumor. Our model predicted that CTL cytotoxicity played only a minor role in tumor control relative to the cytostatic effects of IFNG. Furthermore, our anal-ysis revealed that within B16F10 melanomas HAVCR2 and LAG3 better charac-terize the development of a dysfunctional CTL phenotype than does the PDCD1/CD274 axis.

Automated summary

In this study, the importance of cytolytic versus IFNG-mediated cytostatic effects in a murine melanoma model was compared. The contribution of immune checkpoints HAVCR2, LAG3, and PDCD1/CD274 to CTL exhaustion was also investigated. The results showed that the cytostatic effects of IFNG were more important in tumor control, and HAVCR2 and LAG3 better characterized the development of a dysfunctional CTL phenotype than the PDCD1/CD274 axis.