Anti-Ly6G binding and trafficking mediate positive neutrophil selection to unleash the anti-tumor efficacy of radiation therapy.

Details

Serval ID
serval:BIB_62EF59F96B75
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Anti-Ly6G binding and trafficking mediate positive neutrophil selection to unleash the anti-tumor efficacy of radiation therapy.
Journal
Oncoimmunology
Author(s)
Boivin G., Ancey P.B., Vuillefroy de Silly R., Kalambaden P., Contat C., Petit B., Ollivier J., Bourhis J., Meylan E., Vozenin M.C.
ISSN
2162-402X (Electronic)
ISSN-L
2162-4011
Publication state
Published
Issued date
08/02/2021
Peer-reviewed
Oui
Volume
10
Number
1
Pages
1876597
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
The anti-Ly6G antibody is used to deplete Ly6G <sup>pos</sup> neutrophils and study their role in diverse pathologies. However, depletion is never absolute, as Ly6G <sup>low</sup> neutrophils resistant to depletion rapidly emerge. Studying the functionality of these residual neutrophils is necessary to interpret anti-Ly6G-based experimental designs. In vitro, we found anti-Ly6G binding induced Ly6G internalization, surface Ly6G paucity, and primed the oxidative burst of neutrophils upon TNF α co-stimulation. In vivo, we found neutrophils resistant to anti-Ly6G depletion exhibited anti-neutrophil-cytoplasmic-antibodies. In the pre-clinical Kras <sup>Lox-STOP-Lox-G12D/WT</sup> ; Trp53 <sup>Flox/Flox</sup> mouse lung tumor model, abnormal neutrophil accumulation and aging was accompanied with an N2-like SiglecF <sup>pos</sup> polarization and ly6g downregulation. Consequently, SiglecF <sup>pos</sup> neutrophils exposed to anti-Ly6G reverted to Ly6G <sup>low</sup> and were resistant to depletion. Noting that anti-Ly6G mediated neutrophil depletion alone had no anti-tumor effect, we found a long-lasting rate of tumor regression (50%) by combining anti-Ly6G with radiation-therapy, in this model reputed to be refractory to standard anticancer therapies. Mechanistically, anti-Ly6G regulated neutrophil aging while radiation-therapy enhanced the homing of anti-Ly6G-boundSiglecF <sup>neg</sup> neutrophils to tumors. This anti-tumor effect was recapitulated by G-CSF administration prior to RT and abrogated with an anti-TNFα antibody co-administration. In summary, we report that incomplete depletion of neutrophils using targeted antibodies can intrinsically promote their oxidative activity. This effect depends on antigen/antibody trafficking and can be harnessed locally using select delivery of radiation-therapy to impair tumor progression. This underutilized aspect of immune physiology may be adapted to expand the scope of neutrophil-related research.
Keywords
Anti-neutrophil cytoplasmic antibody (ANCA), depletion resistance, radio-sensitization, tumor-associated-neutrophils (TANs) polarization
Pubmed
Web of science
Open Access
Yes
Create date
09/03/2021 15:46
Last modification date
08/05/2021 6:32
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