The oncolytic peptide LTX-315 triggers immunogenic cell death
Permanent lenke
https://hdl.handle.net/10037/10551Dato
2016-03-10Type
Journal articleTidsskriftartikkel
Peer reviewed
Forfatter
Zhou, Heng; Forveille, Sabrina; Sauvat, Allan; Yamazaki, T; Senovilla, L; Ma, Y; Liu, Peng; Yang, H; Bezu, L; Müller, K; Zitvogel, Laurence; Rekdal, Øystein; Kepp, Oliver; Kroemer, GuidoSammendrag
LTX-315 is a cationic amphilytic peptide that preferentially permeabilizes mitochondrial membranes, thereby causing partially BAX/
BAK1-regulated, caspase-independent necrosis. Based on the observation that intratumorally injected LTX-315 stimulates a strong
T lymphocyte-mediated anticancer immune response, we investigated whether LTX-315 may elicit the hallmarks of immunogenic
cell death (ICD), namely (i) exposure of calreticulin on the plasma membrane surface, (ii) release of ATP into the extracellular space,
(iii) exodus of HMGB1 from the nucleus, and (iv) induction of a type-1 interferon response. Using a panel of biosensor cell lines and
robotized fluorescence microscopy coupled to automatic image analysis, we observed that LTX-315 induces all known ICD
characteristics. This conclusion was validated by several independent methods including immunofluorescence stainings (for
calreticulin), bioluminescence assays (for ATP), immunoassays (for HMGB1), and RT-PCRs (for type-1 interferon induction). When
injected into established cancers, LTX-315 caused a transiently hemorrhagic focal necrosis that was accompanied by massive
release of HMGB1 (from close-to-all cancer cells), as well as caspase-3 activation in a fraction of the cells. LTX-315 was at least as
efficient as the positive control, the anthracycline mitoxantrone (MTX), in inducing local inflammation with infiltration by myeloid
cells and T lymphocytes. Collectively, these results support the idea that LTX-315 can induce ICD, hence explaining its capacity to
mediate immune-dependent therapeutic effects.
Beskrivelse
Published version. Source at http://dx.doi.org/10.1038/cddis.2016.47