Anti-tumor immunity triggered by melphalan is potentiated by melanoma cell surface associated calreticulin

Systemic chemotherapy generally has been considered immunosuppressive, but it has become evident that certain chemotherapeutic drugs elicit immunogenic danger signals in dying cancer cells that can incite protective antitumor immunity. In this study, we investigated whether loco-regionally applied therapies such as melphalan used in limb perfusion for melanoma (Mel-ILP) produces related immunogenic effects. In human melanoma biopsies, Mel-ILP treatment upregulated IL-1B, IL-8 and IL-6 associated with their release in patients’ loco-regional sera. While induction of apoptosis in melanoma cells by melphalan in vitro did not elicit threshold levels of endoplasmic reticulum (ER) and ROS stress associated with danger signals such as induction of cell-surface calreticulin, prophylactic immunization and T cell depletion experiments showed that melphalan administration in vivo could stimulate a CD8+ T cell-dependent protective anti-tumor response.
Interestingly, the vaccination effect was potentiated in combination with exogenous calreticulin, but not tumor necrosis factor, a cytokine often combined with Mel-ILP. Our results illustrate how melphalan triggers inflammatory cell death that can be leveraged by immunomodulators such as the danger signal calreticulin.