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 Jak2KO tumors, but not Jak1KO 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-Jak1KO 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.
journal_name
Sci Transl Medjournal_title
Science translational medicineauthors
Kalbasi A,Tariveranmoshabad M,Hakimi K,Kremer S,Campbell KM,Funes JM,Vega-Crespo A,Parisi G,Champekar A,Nguyen C,Torrejon D,Shin D,Zaretsky JM,Damoiseaux RD,Speiser DE,Lopez-Casas PP,Quintero M,Ribas Adoi
10.1126/scitranslmed.abb0152subject
Has Abstractpub_date
2020-10-14 00:00:00issue
565eissn
1946-6234issn
1946-6242pii
12/565/eabb0152journal_volume
12pub_type
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