Mathematical and experimental models of interactions among subclones and immunity in melanoma

Abstract Melanoma tumors often contain heterogeneous subclones, typically with proliferative or invasive phenotypes. These subclones interact with each other and the immune system to shape tumor progression. Understanding interactions between subclones and the tumor microenvironment is a fundamental challenge for melanoma treatment. To analyze such interactions, we developed dedicated in vivo melanoma mouse and mathematical models. In the experimental models, admixtures of proliferative and invasive subclones of varying proportions were implanted into immunocompromised and immunocompetent mice. Tumor growth and subclone composition were tracked over time. In parallel, we built a computational model to capture the system dynamics. By estimating parameter values of our mathematical model using experimental measurements, we found that, while the proliferative subclone outgrew the invasive subclone, T cell activities selected for the invasive subclone. Initial subclonal proportion in this dynamic system determines the overall tumor sensitivity to immune response. The key interactions identified in this study provide insights into how intratumor heterogeneity and immune pressure influence melanoma progression, suggesting strategies for optimizing individualized therapy.