Abstract Number: OC 41.4
Meeting: ISTH 2021 Congress
Background: Thromboembolism is associated with increased mortality in cancer patients receiving immune checkpoint inhibitors (ICI). The role of thrombin in regulating the T cell response following ICI has not been studied. We hypothesized that thrombin promotes CD8+ T cell functions in the context of ICI therapy.
Aims: Investigate the role of thrombin in the immune response following ICI therapy.
Methods: We subcutaneously inoculated B16 melanoma cells into C57Bl/6 mice in which circulating prothrombin was reduced to 10% of normal using an established prothrombin ASO, or appropriate controls. Once tumors were palpable, the animals were treated with an anti-PD1 antibody or control IgG. We analyzed the role of thrombin and PAR-1, -2 and -4 in CD8+ T cell cytokine production and proliferative capacity in vitro.
Results: Anti-PD1 therapy significantly limited tumor growth in mice with normal prothrombin levels. However, anti-PD1 therapy failed to reduce tumor growth in mice with lowered prothrombin expression. Anti-PD1 therapy resulted in significantly greater frequencies of CD8+ TILs in tumors harvested from mice with normal prothrombin levels, but not in tumors from mice with low prothrombin levels. In vitro studies showed that WT CD8+ T cells stimulated with CD3/CD28 in the presence of thrombin demonstrated a dose-dependent increase in survival and cytokine production. Genetic deletion of either PAR-1 or PAR-4 diminished the impact of thrombin, but PAR-4 appears to be the primary thrombin target driving T cell proliferation. Our data also suggest that PAR-2 limits T cell proliferation and cytokine productions, and PAR-1 transactivation of PAR-2 is a mechanism driving PAR-2 activation.
Conclusions: Thrombin promotes the anti-tumor response following anti-PD1 treatment. We identified the capacity for thrombin-mediated PAR-1 transactivation to limit cytokine producing CD8+ T cells, and a role for PAR-4 activation to enhance proliferation of CD8+ T cells.
To cite this abstract in AMA style:Cantrell R, Rosenfeldt L, Sharma BK, Gourley B, Revenko A, Monia B, Palumbo J. The Role of the Thrombin/PAR Axis in the Anti-tumor CD8+ T Cell Response Following Immune Checkpoint Inhibition Therapy [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/the-role-of-the-thrombin-par-axis-in-the-anti-tumor-cd8-t-cell-response-following-immune-checkpoint-inhibition-therapy/. Accessed August 16, 2022.
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