Research ArticleCancer

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

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Science Translational Medicine  14 Oct 2020:
Vol. 12, Issue 565, eabb0152
DOI: 10.1126/scitranslmed.abb0152

Interfering with cancer

Many immunotherapies for cancer have emerged in recent years, but none are universally effective. One potential problem is the loss of interferon signaling in tumors, which impairs the effectiveness of both immune checkpoint blockade and cell-based therapies. Kalbasi et al. determined that both JAK1 and JAK2 signaling were essential for the success of immune checkpoint blockade, whereas cell-based therapy only required JAK1 function, which maintained sufficient interferon signaling. The authors showed that defective interferon signaling in tumors could be bypassed with the immunostimulatory compound BO-112. In a companion clinical trial, Márquez-Rodas et al. tested BO-112 in human patients with cancer, with or without immune checkpoint blockade.


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.

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