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

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.

Intratumoural administration and tumour tissue targeting of cancer immunotherapies

“…Intratumoural BO-112 has antitumour activity in mouse models 64 . In addition to TLR3, BO-112 activates the cytoplasmic RGR family RNA helicases MDA-5 and RIG-I 65 and potentially also protein kinase R (PKR), which is another cytoplasmic PRR for dsRNA 66 . Notably, following intratumoural delivery, this compound kills a fraction of tumour cells through mechanisms that reportedly include intense autophagy 65 .…”

MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

“…Upregulation of IFNγ signature early during therapy correlated with improved outcomes of immune checkpoint blockade in melanoma [75]. Mutations in the IFNγ receptor IFNGR1 [76], signaling adaptors JAK1 and JAK2 [63,65,77,78] or components of the IFNγ signaling cascade, such as STAT1 and IRF1 [79,80] were associated with cancer progression and immunotherapy resistance. Yet in melanoma and lung cancer-the two cancers where cancer evolution during immunotherapy is studied best-genetic alterations in IFNγ signaling pathways were relatively uncommon [60,[63][64][65] and some of the mutations (such as in STAT1) occurred in both responders and non-responders [60,81,82], indicating that loss of INFγ responsiveness does not necessarily favor tumor progression.…”

“…The relevance of these findings in a broader context of EMT in cancer is unclear, although we and others have demonstrated a mechanistic link between EMT and impaired MHC-I expression or induction in melanoma [93], prostate cancer [94] and a mouse model of mammary carcinoma [95], through the upregulation of the transcription factor Snail driving activation of transforming growth factor (TGF)β and suppression of NF-kB signaling [93,94]. Overexpression of NLRC5 in tumor cells can dramatically enhance their immunogenicity, such as overexpression of Nlrc5 in a mouse model of melanoma resulted in improved tumor clearance [78]. Finally, radiation appears to be able to induce MHC-I expression by directly upregulating NLRC5, as well as by activating interferon signaling [96].…”

Acquired Resistance to Immune Checkpoint Blockades: The Underlying Mechanisms and Potential Strategies

“…Kalbasi et al. reported that 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 MHC-I expression ( 146 ).…”

“…reported that ACT was effective against tumors with JAK2 loss ( 146 ). As tumors with JAK1 loss show significant downregulation of MHC-I, ACT combined with overexpression of NLRC5 or intratumoral delivery of BO-112 was an effective approach ( 146 ). As for the IFN-β induced resistance, IFN-β inhibition might be an effective strategy.…”