Abstract
IFN-inducible endogenous retroviruses promote mesenchymal tumor cell–mediated immunosuppression.
Major finding: IFN-inducible endogenous retroviruses promote mesenchymal tumor cell–mediated immunosuppression.
Mechanism: Loss of EZH2-driven repression of SPARCS activates IFN-mediated innate immune pathways.
Impact: Therapeutic targeting of the SPARCS positive feedback loop may enhance cancer immunotherapy.
Activated RAS/MET signaling or chemotherapy induces the epithelial-to-mesenchymal transition in small-cell lung cancer (SCLC), which subsequently promote chemoresistance and produces protumorigenic cytokines. To further characterize mesenchymal SCLC, Cañadas and colleagues evaluated a mesenchymal subpopulation of H69 SCLC cells (H69M) and revealed that, compared to H69 cells, RAS signaling was elevated in H69M cells, and critical components of the innate immunity system, such as TBK1 and IRF3, as well as cytokines/chemokines were increased in PD-L1hi and CD44hi subpopulations of H69M cells. PD-L1hi H69M cells reverted phenotypically, but not genomically, to H69 cells, suggesting that innate immunity was epigenetically activated. Expression analysis of endogenous retroviral elements (ERV), which are epigenetically silenced, identified IFNγ-inducible antisense 3′-UTR ERVs, called SPARCS, in genes enriched for STAT1 motifs in PD-L1hi H69M cells. Further, PD-L1hi H69M cells exhibited increased upregulation of cytosolic double-stranded RNA (dsRNA) sensing pathways, which activate IFN. Chemoresistant mesenchymal H69 (H69AR), but not parental H69, cells exhibited IFNγ-induced PD-L1 expression and increased chromatin accessibility around SPARCS loci; moreover, EZH2, which was downregulated in H69AR and H69M cells, was shown to repress IFN-stimulated SPARCS expression in parental H69 cells. Exogenous IFNγ simultaneously induced expression of SPARCS-derived dsRNA and increased levels of activated TBK1 and IRF3, subsequently increasing SPARCS expression, TBK1 activation, and effector cytokine production in H69AR cells, suggesting that SPARCS amplifies the IFN-mediated innate immune signaling feedback loop. Expression of a SPARCS gene signature was enriched in other cancer types, such as renal cell carcinoma and glioblastoma, and correlated with that of genes related to epigenetic regulation, innate immunity, and RTK/KRAS signaling. Two patient-derived KRASmut lung tumor organoids exhibited T-cell infiltration, but only the SPARCShi organoids exhibited increased cytokine production and sensitivity to immune checkpoint blockade after IFNγ treatment. These findings identify a subclass of ERVs that promotes innate immunity in mesenchymal cells and suggest potential approaches to immunotherapy combination therapy.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.