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. 2015 Apr 15;75(8):1603-14.
doi: 10.1158/0008-5472.CAN-14-2089. Epub 2015 Mar 11.

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

Aleksandra M Dudek-Perić  1 , Gabriela B Ferreira  2 , Angelika Muchowicz  3 , Jasper Wouters  4 , Nicole Prada  5 , Shaun Martin  1 , Santeri Kiviluoto  6 , Magdalena Winiarska  3 , Louis Boon  7 , Chantal Mathieu  2 , Joost van den Oord  4 , Marguerite Stas  8 , Marie-Lise Gougeon  5 , Jakub Golab  9 , Abhishek D Garg  10 , Patrizia Agostinis  10
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Antitumor immunity triggered by melphalan is potentiated by melanoma cell surface-associated calreticulin

Aleksandra M Dudek-Perić et al. Cancer Res. .

Abstract

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 locoregionally applied therapies, such as melphalan, used in limb perfusion for melanoma (Mel-ILP) produce related immunogenic effects. In human melanoma biopsies, Mel-ILP treatment upregulated IL1B, IL8, and IL6 associated with their release in patients' locoregional sera. Although induction of apoptosis in melanoma cells by melphalan in vitro did not elicit threshold levels of endoplasmic reticulum and reactive oxygen species 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 antitumor 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.

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