Resistance of Cancers to Immunologic Cytotoxicity and Adoptive Immunotherapy via X-Linked Inhibitor of Apoptosis Protein Expression and Coexisting Defects in Mitochondrial Death Signaling

Abstract

The ability of cancers to evade immune surveillance and resist immunotherapy raises a fundamental question of how tumor cells survive in the presence of a competent immune system. Studies to address this question have primarily focused on mechanisms by which tumor cells avoid recognition by or induce tolerance in the immune system. However, little is known about whether cancer cells also acquire an intrinsic ability to resist killing by immune effectors. We find that cancer cells enhance their ability to withstand an attack by cytotoxic immune effector cells via acquisition of specific genetic alterations that interfere with the shared mitochondrial death signaling pathway entrained by granzyme B, IFN-;, and Apo2 ligand/tumor necrosis factor-related apoptosis inducing ligand (Apo2L/TRAIL), three key mediators of immunologic cell-mediated cytotoxicity. We show that the coexistence of specific mitochondrial signaling defects (either deletion of Bax, overexpression of Bcl-x L , or deletion of Smac) with expression of X-linked inhibitor of apoptosis protein decreases the sensitivity of cancer cells to IFN-;/Apo2L/ TRAIL-or granzyme B-induced apoptosis, lymphocytemediated cytotoxicity in vitro, and adoptive cellular immunotherapy in vivo. Conversely, negating X-linked inhibitor of apoptosis protein expression or function in tumor cells with defective mitochondrial signaling enables direct activation of caspase-3/-7 by granzyme B or Apo2L/TRAIL, and restores their susceptibility to immunologic cytotoxicity. These findings identify an important mechanism by which cancers evade elimination by immune effector cells and suggest that cancer immunotherapy might be improved by concurrent strategies to alleviate or circumvent the intrinsic mitochondrial death signaling defects that help cancer cells resist immunologic cytotoxicity.

A mitochondrial block and expression of XIAP lead to resistance to TRAIL-induced apoptosis during progression to metastasis of a colon carcinoma

“…Indeed, granzyme-B transduces death signals either by cleaving Bid to generate gtBid and activate the mitochondrial pathway or by directly cleaving procaspase-3 such as caspase-8. It has been shown that coexisting defects in mitochondrial death signalling together with expression of XIAP induce resistance to immunological cytotoxicity and adoptive immunotherapy (Ravi et al, 2006). Thus, these properties would confer the ability to escape immune surveillance on metastatic cells.…”

The Proteasome Inhibitor Bortezomib Sensitizes Melanoma Cells toward Adoptive CTL Attack

“…To reach the critical level of executioner caspases, the release of additional proapoptotic factors such as second mitochondria-derived activator of caspase (SMAC) from the mitochondria is necessary to displace XIAP (X-linked inhibitor of apoptosis protein) from partially processed caspases, thus completing caspase autoactivation (7,8). Elevated XIAP expression or dysfunctional mitochondrial apoptotic pathways in tumor cells are likely responsible for the inadequate caspase activation observed during failed CTL attacks (9,10). The efficacy of adoptive CTL transfer may therefore be improved by restoring the defective mitochondrial apoptotic pathways in tumor cells.…”

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

“…In fact, besides activating the NF-KB pathway it is also believed to signal through MAPK, JNK and p38 (Varfolomeev et al, 2005). The NF-KB induction has been correlated with TRAIL resistance in multiple cell lines, supporting the proposal of its activity as TRAIL-regulatory (Ravi et al, 2006, Zwacka et al, 2000.…”