Immunogenic cell death (ICD) constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. Only a few agents can elicit bona fide ICD, including some clinically established drugs such as the proteasome inhibitor bortezomib, as demonstrated in malignant myeloma and mantle cell lymphoma, but not yet in melanoma.
We show that bortezomib causes ICD in vitro through induction of endoplasmic reticulum stress, autophagy and apoptosis and through translocation and/or secretion of damage-associated molecular patterns (DAMPs). Vaccination with bortezomib-treated dead melanoma cells induced tumour immunogenicity in vivo, as evidenced in a significant reduction/delay of tumour formation after challenge with live cells. Intralesional injection of bortezomib synergised with subsequent systemic treatment with immune checkpoint inhibition using CTLA-4 and PD-1 antagonists. Re-challenge demonstrated long-term protection through bortezomib combined with immune checkpoint inhibition. Polyfunctional T cell assays revealed that intralesional bortezomib injection generates a tumour-specific T cell response. Importantly, immune checkpoint inhibitor-resistance was reverted by bortezomib-induced immunogenicity. Bortezomib induces ER stress and apoptosis, enhances ICD markers (DAMPs) in vitro and is immunogenic in vivo. Bortezomib-induced ICD is a good strategy to recruit the inflammatory immune response. Bortezomib-induced ICD enhances response to immune checkpoint inhibitors, even in ICI-resistant tumours. We propose intralesional injection of bortezomib combined with systemic CTLA-4 and PD-1 antagonists to improve immune therapy in melanoma.

LB043 - Overcoming Immune Checkpoint Inhibitor Resistance to Improve Melanoma Therapy

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.