Hemostasis and tumor immunity

Abstract

Significant data have accumulated demonstrating a reciprocal relationship between cancer and the hemostatic system whereby cancer promotes life-threatening hemostatic system dysregulation (e.g., thromboembolism, consumptive coagulopathy), and hemostatic system components directly contribute to cancer pathogenesis. The mechanistic underpinnings of this relationship continue to be defined, but it is becoming increasingly clear that many of these mechanisms involve crosstalk between the hemostatic and immune systems. This is perhaps not surprising given that there is ample evidence for bidirectional crosstalk between the hemostatic and immune systems at multiple levels that likely evolved to coordinate the response to injury, host defense, and tissue repair. Much of the data linking hemostasis and immunity in cancer biology focus on innate immune system components. However, the advent of adaptive immunity-based cancer therapies such as immune checkpoint inhibitors has revealed that the relationship of hemostasis and immunity in cancer extends to the adaptive immune system. Adaptive immunity-based cancer therapies appear to be associated with an increased risk of thromboembolic complications, and hemostatic system components appear to regulate adaptive immune functions through diverse mechanisms to affect tumor progression. In this review, the evidence for crosstalk between hemostatic and adaptive immune system components is discussed, and the implications of this relationship in the context of cancer therapy are reviewed. A better understanding of these relationships will likely lead to strategies to make existing adaptive immune based therapies safer by decreasing thromboembolic risk and may also lead to novel targets to improve adaptive immune-based cancer treatments.

Keywords: cancer; hemostasis; immune system; thromboembolism; tumor.

FIGURE 1

Graphical summary of the proposed mechanistic crosstalk between adaptive immunity and hemostasis in cancer. (A) Thrombin‐mediated activation of tumor cell‐associated PAR‐1 and factor Xa‐mediated activation of TAM‐associated PAR‐2 downregulate T‐cell effector functions, limiting adaptive tumor immunity. Thrombin‐mediated activation of T cell‐associated PAR‐1 has been linked to upregulation of T‐cell effector functions in other contexts, but whether this pathway plays a role in adaptive tumor immunity remains to be determined. See text for details. (B) Upregulation of adaptive tumor immunity could promote thrombosis through multiple mechanisms. Killing of tumor cells could result in release of TF‐expressing microvesicles. T cell activation has been shown to result in upregulation of monocyte/macrophage TF expression in vitro. Whether this mechanism is relevant in the context of cancer remains to be determined. Increased circulating levels of IL‐8 have been associated with an increased incidence of thrombosis in patients receiving ICI therapy. IL‐8 has been shown to promote NETosis in myeloid derived suppressor cells (MDSC), providing a potential link between IL‐8 and thrombosis. See text for details