Dormant Tumor Cell Vaccination: A Mathematical Model of Immunological Dormancy in Triple-Negative Breast Cancer

Simple Summary Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, particularly affecting young women. Chemotherapy is the main choice for the treatment of these patients. It has been shown that some chemotherapies induce immunogenic cell death and elicit an adaptive cytotoxic T cell immune response through the activation of the type I interferon pathway. We made an evolutionary mathematical model based on the recently reported in vivo induction of immunological tumor dormancy of a murine TNBC cell line upon in vitro treatment with chemotherapy. Our model replicates the previously obtained experimental results and predicts a prophylactic and therapeutic vaccination effect by injecting dormant cells with active type I interferon signaling, before or after challenge with the aggressive parental tumor cells, respectively. These results show the potential of a dormant tumor cell-based therapy inducing an adaptive immune response, suppressing tumor growth. Triple-negative breast cancer (TNBC) is a molecular subtype of breast malignancy with a poor clinical prognosis. There is growing evidence that some chemotherapeutic agents induce an adaptive anti-tumor immune response. This reaction has been proposed to maintain the equilibrium phase of the immunoediting process and to control tumor growth by immunological cancer dormancy. We recently reported a model of immunological breast cancer dormancy based on the murine 4T1 TNBC model. Treatment of 4T1 cells in vitro with high-dose chemotherapy activated the type I interferon (type I IFN) signaling pathway, causing a switch from immunosuppressive to cytotoxic T lymphocyte-dependent immune response in vivo, resulting in sustained dormancy. Here, we developed a deterministic mathematical model based on the assumption that two cell subpopulations exist within the treated tumor: one population with high type I IFN signaling and immunogenicity and lower growth rate; the other population with low type I IFN signaling and immunogenicity and higher growth rate. The model reproduced cancer dormancy, elimination, and immune-escape in agreement with our previously reported experimental data. It predicted that the injection of dormant tumor cells with active type I IFN signaling results in complete growth control of the aggressive parental cancer cells injected at a later time point, but also of an already established aggressive tumor. Taken together, our results indicate that a dormant cell population can suppress the growth of an aggressive counterpart by eliciting a cytotoxic T lymphocyte-dependent immune response.

Automated summary

Triple-negative breast cancer is an aggressive subtype affecting young women, with chemotherapy as the main treatment choice. Some chemotherapies have been shown to induce immunogenic cell death and elicit an adaptive immune response. Mathematical modeling predicts a prophylactic and therapeutic vaccination effect by injecting dormant cells with active interferon signaling. This approach shows potential in suppressing tumor growth through an adaptive immune response.