Bortezomib Induces Immunogenic Cell Death in Multiple Myeloma

Abstract

As a general rule, successful antineoplastic treatments induce an antitumor immune response, even if they were initially designed to target cancer cell-autonomous pathways. In this issue of Blood Cancer Discovery, Gulla and colleagues reveal that the proteasome inhibitor bortezomib induces immunogenic stress and death in multiple myeloma cells, thus explaining its therapeutic efficacy. See related article by Gulla et al., p. 468.

Figure 1.

Hypothetical cascade of molecular, cellular, and immunologic effects of bortezomib. In MM cells, bortezomib induces CALR exposure, as well as a type-1 interferon (IFN) response. Several of the signaling elements involved in the cascade are shown. Note that knockout of the CALR gene abolishes the induction of a type-1 IFN response. However, the level at which this latter response is abolished is elusive, as indicated by the question mark. ICD then results in an anti-MM immune response that is required for bortezomib to be efficient in vivo. Several elements of the cascade have prognostic impact on patients with MM treated with bortezomib. Molecules and processes that are required for optimal bortezomib effects in mice (CALR, STING, IFNAR, immune response) are marked in red. For details, see the main text.