A serious and life-threatening cancer-associated sequelae is venous thromboembolism (VTE). Indeed, VTE is the second leading cause of death in cancer patients, second only to the malignancy itself. Cancer patients with VTE or at high risk for VTE are generally treated with anticoagulants, which limit thrombin generation. While it's been widely accepted that thrombin plays a role in cancer progression, the effects thrombin has on other cell types within the tumor microenvironment (TME) have not been thoroughly studied.
An understudied role of thrombin may be found in its ability to drive T cell functions. Recently, we have identified thrombin as a potential enhancer of CD8+ T cell effector functions by signaling through the protease activated receptor 1 (PAR-1). Our preliminary data shows that thrombin increases CD8+ T cell survival in a PAR-1 dependent fashion. CD8+ tumor infiltrating lymphocytes (TILs) play a critical role in tumor clearance through their cytolytic and anti-tumor cytokine producing capacity. However, the hostile tumor microenvironment (TME) promotes a gradual reduction in CD8+ TIL capacity to produce cytokines and kill targets. Specific components of the TME, including PDL1 expression, are associated with loss of T cell functionality. A promising strategy to block the interaction of CD8+ TILs and the inhibitory TME components is immune checkpoint inhibition (ICI) therapy, as shown by effective blockade of PD1 signaling by anti-PD1 antibodies. However, these ICI therapies leave many patients unresponsive, highlighting the necessity to uncover additional underlying mechanisms involved in modulating CD8+ T cell responses against cancer. Our preliminary findings lead us to hypothesize that thrombin, in conjunction with PD1 blockade, may work in synergy to promote CD8+ T cell killing of tumors.
Consistent with our hypothesis, preliminary results suggest that thrombin is necessary for a robust anti-tumor immune response following ICI in vivo. Here, cohorts of C57BL/6 mice with low or normal circulating prothrombin levels bearing B16 tumors were treated with an anti-PD1 antibody or control IgG. Anti-PD1 therapy significantly limited tumor growth in mice with normal prothrombin levels, but had no impact on tumor growth in mice with low prothrombin levels.
A major implication of our findings is that limiting thrombin generation with anticoagulants may be detrimental in the context of immune checkpoint inhibition treatment. Better defining the potential risk of reducing ICI efficacy by concurrent treatment with anticoagulants will require a detailed understanding of the role thrombin plays in cancer immunobiology.
Disclosures
Revenko: Ionis Pharmaceuticals: Employment. Monia:Ionis Pharmaceuticals: Employment. Palumbo:Ionis Pharmaceuticals: Research Funding.
Immune Checkpoint Modulation in Colorectal Cancer: What’s New and What to Expect
