The immunogenicity of tumor cell death

Abstract

It is an ongoing conundrum under which circumstances cellular demise induces an immune response and whether apoptotic or necrotic cells are intrinsically immunogenic or tolerogenic. This review summarizes recent insights in the immunogenicity of dying tumor cells. Although apoptosis appears to be morphologically homogeneous, recent evidence suggests that the preapoptotic surface exposure of calreticulin (CRT) may have a profound impact on the immune response. Moreover, the release of high mobility group box 1 protein (HMGB1) during late apoptosis promotes antigen processing by dendritic cells and hence contributes to efficient antigen presentation and cytotoxic T-cell activation. HMGB1 is sensed by TLR4 on dendritic cells, and loss-of-function alleles of TLR4 abolish anticancer immune response and accelerate tumor progression. A combination of signals elicits an efficient immune response against tumor cells that are dying in response to anthracyclines or ionizing irradiation. During early apoptosis, caspase activation and endoplasmic reticulum stress facilitate the surface exposure of immunogenic effectors followed by the release of soluble factors that are indispensable for effective immune response. Failure of tumor cells to expose/secrete such immunogenic factors and/or failure of the immune system to sense such effectors may compromise the efficacy of conventional anticancer therapies.