Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma.

Details

Serval ID
serval:BIB_CF3704461FDA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma.
Journal
Science translational medicine
Author(s)
Kalbasi A., Tariveranmoshabad M., Hakimi K., Kremer S., Campbell K.M., Funes J.M., Vega-Crespo A., Parisi G., Champekar A., Nguyen C., Torrejon D., Shin D., Zaretsky J.M., Damoiseaux R.D., Speiser D.E., Lopez-Casas P.P., Quintero M., Ribas A.
ISSN
1946-6242 (Electronic)
ISSN-L
1946-6234
Publication state
Published
Issued date
14/10/2020
Peer-reviewed
Oui
Volume
12
Number
565
Pages
eabb0152
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Defects in tumor-intrinsic interferon (IFN) signaling result in failure of immune checkpoint blockade (ICB) against cancer, but these tumors may still maintain sensitivity to T cell-based adoptive cell therapy (ACT). We generated models of IFN signaling defects in B16 murine melanoma observed in patients with acquired resistance to ICB. Tumors lacking Jak1 or Jak2 did not respond to ICB, whereas ACT was effective against Jak2 <sup>KO</sup> tumors, but not Jak1 <sup>KO</sup> tumors, where both type I and II tumor IFN signaling were defective. This was a direct result of low baseline class I major histocompatibility complex (MHC I) expression in B16 and the dependency of MHC I expression on either type I or type II IFN signaling. We used genetic and pharmacologic approaches to uncouple this dependency and restore MHC I expression. Through independent mechanisms, overexpression of NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) and intratumoral delivery of BO-112, a potent nanoplexed version of polyinosinic:polycytidylic acid (poly I:C), each restored the efficacy of ACT against B16-Jak1 <sup>KO</sup> tumors. BO-112 activated double-stranded RNA (dsRNA) sensing (via protein kinase R and Toll-like receptor 3) and induced MHC I expression via nuclear factor κB, independent of both IFN signaling and NLRC5. In summary, we demonstrated that in the absence of tumor IFN signaling, MHC I expression is essential and sufficient for the efficacy of ACT. For tumors lacking MHC I expression due to deficient IFN signaling, activation of dsRNA sensors by BO-112 affords an alternative approach to restore the efficacy of ACT.
Keywords
tumor immunology, interferon, antigen presentation
Pubmed
Open Access
Yes
Create date
31/10/2020 15:10
Last modification date
16/02/2021 7:26
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