Despite the unprecedented success of immune checkpoint inhibitors (ICI) in cancer therapy, one major unresolved dilemma is treatment resistance. Immunogenic cell death (ICD) constitutes a prominent pathway for the activation of anti-cancer immunity, which in turn determines the long-term success of anticancer therapies. Only a few agents can elicit bona fide ICD, including 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 apoptotic melanoma cells induced tumor immunogenicity in vivo. Intralesional injection of bortezomib synergized with subsequent systemic treatment with ICI. Re-challenge demonstrated long-term protection through bortezomib combined with ICI. Polyfunctional T cell assays revealed that intralesional bortezomib injection generates a tumor-specific T cell response. Importantly, ICI resistance was reverted by bortezomib-induced immunogenicity.
Bortezomib induces ICD in vitro and immunogenicity in vivo. Bortezomib-induced ICD recruits inflammatory immune response to the tumor site. Bortezomib-induced ICD improves ICI treatment and reverts resistance re-sensitizing mice refractory to ICI. We propose intralesional injection of bortezomib followed by systemic ICI to improve immune therapy in melanoma.