Plasminogen activating inhibitor-1 (PAI-1) is associated with poor clinical outcomes in cancer patients, and elevated levels of PAI-1 in both tissue and serum are correlated with poor response to therapy in various cancers, including skin cancer. PAI-1 is reported as a key regulator of PD-L1 expression on melanoma cells through endocytosis, leading to abrogating the efficacy of anti-PD1 antibodies (Abs). These findings suggested that PAI-1 expression might predict the efficacy of anti-PD1 Abs. From the above findings, at first, we evaluated the expression and production of PAI-1 in melanoma patients who treated with anti-PD1 Abs, and then, we investigated the immunomodulatory effects of PAI-1 on tumor-associated macrophages in vitro. Immunohistochemical staining of PAI-1 showed that PAI-1 expression on melanoma cells was significantly decreased in anti-PD1 Abs responded patients compared to non-responded patients. Moreover, baseline serum levels of PAI-1 were significantly decreased in anti-PD1 Abs responded patients compared to non-responded patients. Notably, PAI-1 decreased the production of various chemokines from monocyte-derived M2 macrophages in vitro, suggesting that PAI-1 might decrease tumor-infiltrating lymphocytes to hamper the anti-tumor effects of anti-PD1 Abs. To further confirm this hypothesis, we investigated the anti-tumor effects of PAI-1 inhibitors (TM5614) in combination with anti-PD1 Abs using B16F10 mouse melanoma model. The co-administration of TM5614 augmented the therapeutic effect of anti-PD1 Abs on the treatment of B16F10 melanoma. These results suggest that TM5614 might enhance the therapeutic effects of nivolumab in patients with advanced melanoma, and phase II study investigating the safety and efficacy of TM5614 in combination with nivolumab in the treatment of unresectable malignant melanoma is now ongoing (jRCT2021210029).

ESDR447 - Development of the combination therapy of anti-PD1 antibody with PAI-1 inhibitors in advanced melanoma patients

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.