The antimicrobial peptide Defensin cooperates with Tumour Necrosis Factor to drive tumour cell death in Drosophila

Abstract

23Antimicrobial peptides (AMPs) are small cationic molecules best known as 24 mediators of the innate defence against microbial infection. While in vitro and 25 ex vivo evidence suggest AMPs' capacity to kill cancer cells, in vivo 26 demonstration of an anti-tumour role of endogenous AMPs is lacking. Using a 27Drosophila model of tumourigenesis, we reveal a role for the AMP Defensin in 28 the control of tumour progression. Our results reveal that Tumour Necrosis 29Factor mediates exposure of phosphatidylserine (PS), which makes tumour 30 cells selectively sensitive to the action of Defensin remotely secreted from 31 tracheal and fat tissues. Defensin binds tumour cells in PS-enriched areas, 32provoking cell death and tumour regression. Altogether, our results provide 33 the first in vivo demonstration for a role of an endogenous AMP as an anti-34 cancer agent, as well as a mechanism that explains tumour cell sensitivity to 35 the action of AMPs. 36 37 38

The role of innate immunity in the protection conferred by a bacterial infection against cancer: study of an invertebrate model

“…In this context, our study demonstrates that naturally occurring bacterial infection can promote tumor regression in two drosophila tumor models, and it supports the idea that infection-dependent production of diptericin and drosomycin, two antimicrobial peptides, may be key drivers of this regression through increased tumor cell death. Our results are supported by previous studies showing that increase in Toll and Imd signaling in tissues distant from the tumor result in increased tumor cell death in dlg mutant animals [37][38][39] . Imd and Toll pathways could act synergistically to produce AMP, as already reported elsewhere 40 .…”

“…However, the striking rise in immunotherapeutic strategies over the few past decades, exemplified by the attribution of the 2018 Nobel Prize in Medicine, calls for a re-evaluation of mechanisms linking infections and spontaneous tumor regression. While studies have mainly focused on adaptive immunity for the elaboration of new drugs 47 , our study, together with other recent studies in flies 38,39 , has revealed some molecular aspects mediating the forgotten potential of the innate immune system in the control of tumor burden. Further efforts should be made to elucidate the precise molecular mechanisms leading to cancer regression in response to innate immune system activation: this may also help with the design of new therapeutic strategies using drugs that mimic the effect of infections to establish an innate immune profile adverse to cancer cells.…”

“…For dlg mutant larvae, tumors were dissected in PBS seven days after eclosion, fixed in 4% formaldehyde, and immunostained with 4′,6-diamidine-20-phenylindole dihydrochloride (DAPI) (sigma) and rabbit anti-cleaved decapping protein 1 (Dcp1) (Cell Signaling Technology) antibody as previously described 38 . Tissues were imaged at optimal slice parameters and 12-bit resolution using a Zeiss 710 confocal microscope.…”

“…Tissues were imaged at optimal slice parameters and 12-bit resolution using a Zeiss 710 confocal microscope. We then used Volocity 3D imaging analysis software (Perkin Elmer) to quantify total tumor volume identified by DAPI staining and cell death visualized with anti-Dcp1 staining, as described in 38 .…”

Synergy and remarkable specificity of antimicrobial peptides in vivo using a systematic knockout approach

“…Their expression is induced to very high levels upon challenge to provide microbicidal concentrations in the μM range. Numerous studies have revealed unique roles that AMPs may play in host physiology including anti-tumor activity (Suttmann et al, 2008; Kuroda et al, 2015; Araki et al, 2018; Parvy et al, 2019), inflammation in aging (Cao et al, 2013; Kounatidis et al, 2017; E et al, 2018), involvement in memory (Bozler et al, 2017; Barajas-Azpeleta et al, 2018), mammalian immune signaling (van Wetering et al, 2002; Tjabringa et al, 2003), wound-healing (Tokumaru et al, 2005; Chung et al, 2017), regulation of the host microbiota (Login et al, 2011; Mergaert et al, 2017), tolerance to oxidative stress (Zhao et al, 2011; Zheng et al, 2007), and of course microbicidal activity (Imler and Bulet, 2005; Wimley, 2010). The fact that AMP genes are immune inducible and expressed at high levels has led to the common assumption they play a vital role in the innate immune response.…”