A Role of Effector CD 8 + T Cells Against Circulating Tumor Cells Cloaked with Platelets: Insights from a Mathematical Model.

Abstract

Cancer metastasis accounts for a majority of cancer-related deaths worldwide. Metastasis occurs when the primary tumor sheds cells into the blood and lymphatic circulation, thereby becoming circulating tumor cells (CTCs) that transverse through the circulatory system, extravasate the circulation and establish a secondary distant tumor. Accumulating evidence suggests that circulating effector CD $8^{+}$ T cells are able to recognize and attack arrested or extravasating CTCs, but this important antitumoral effect remains largely undefined. Recent studies highlighted the supporting role of activated platelets in CTCs's extravasation from the bloodstream, contributing to metastatic progression. In this work, a simple mathematical model describes how the primary tumor, CTCs, activated platelets and effector CD $8^{+}$ T cells participate in metastasis. The stability analysis reveals that for early dissemination of CTCs, effector CD $8^{+}$ T cells can present or keep secondary metastatic tumor burden at low equilibrium state. In contrast, for late dissemination of CTCs, effector CD $8^{+}$ T cells are unlikely to inhibit secondary tumor growth. Moreover, global sensitivity analysis demonstrates that the rate of the primary tumor growth, intravascular CTC proliferation, as well as the CD $8^{+}$ T cell proliferation, strongly affects the number of the secondary tumor cells. Additionally, model simulations indicate that an increase in CTC proliferation greatly contributes to tumor metastasis. Our simulations further illustrate that the higher the number of activated platelets on CTCs, the higher the probability of secondary tumor establishment. Intriguingly, from a mathematical immunology perspective, our simulations indicate that if the rate of effector CD $8^{+}$ T cell proliferation is high, then the secondary tumor formation can be considerably delayed, providing a window for adjuvant tumor control strategies. Collectively, our results suggest that the earlier the effector CD $8^{+}$ T cell response is enhanced the higher is the probability of preventing or delaying secondary tumor metastases.