Modeling Combination Chemo-Immunotherapy for Heterogeneous Tumors

Abstract

Hypermutable cancers create opportunities for the development of various immunotherapies, such as immune checkpoint blockade (ICB) therapy. However, emergent studies have revealed that many hypermutated tumors have poor prognosis due to heterogeneous tumor antigen landscapes, yet the underlying mechanisms remain poorly understood. To address this issue, we developed mathematical models to explore the impact of combining chemotherapy and ICB therapy on heterogeneous tumors. Our results uncover how chemotherapy reduces antigenic heterogeneity, creating improved immunological conditions within tumors, which, in turn, enhances the therapeutic effect when combined with ICB. Furthermore, our results show that the recovery of the immune system after chemotherapy is crucial for enhancing the response to chemo-ICB combination therapy. Author summaryThe challenge posed by intratumoral heterogeneity is gaining recognition in the field of cancer treatment. Despite the success of immune checkpoint blockade (ICB) therapies in enhancing overall survival across various cancer types, the complexity of therapeutic responses persists due to the heterogeneity of tumor antigens. In this study, we developed mathematical models to explore the evolutionary dynamics of tumors with both homogeneous and heterogeneous antigen landscapes. Our analysis reveals that tumors with heterogeneity exhibit resistance to ICB therapy, unlike their homogeneous counterparts which respond positively. Additionally, our models demonstrate that early treatment of heterogeneous tumors with chemotherapy leads to significant remission but also rapid recurrence. Notably, we identified a fascinating trade-off associated with chemotherapy--while suppressing the immune system, it creates a tumor immunological environment that becomes more conducive to ICB therapy. Finally, our modeling highlights the augmented response observed in tumors subjected to a chemo-ICB combination and shows the crucial role of immune recovery in the context of combination therapy.