Oncogene-targeted agents induce an interferon response in EGFR and EML4-ALK driven lung cancer
Natalia J. Gurule1, Caroline McCoach3, Trista K. Hinz1, Lindsay Marek1, Karen Ryall2, Sean Korpela1, Dan Sisler1, Aik-Choon Tan2, Robert A. Doebele2* and Lynn E. Heasley1*
Department of Craniofacial Biology, School of Dental Medicine1, Department of Medical Oncology2, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO; Thoracic Medical Oncology, Helen Diller Comprehensive Cancer Center, UCSF, San Francisco, CA3
Immunotherapy drugs that target immune evasion, a hallmark of cancer, have significantly impacted a subset of patients with lung cancer. However, patients with EGFR mutant and EML4-ALK positive lung cancer receive little benefit from these therapies. A growing literature demonstrates that a type I interferon (IFN) response mediating T cell infiltration into the tumor microenvironment (TME) is required for immunotherapy efficacy. We observe that oncogenic EGFR and ALK cause a suppression of IFN signaling within the TME, as evidenced by an induction of interferon stimulated genes (ISGs) including STAT1, STAT2, IFIT1, IFIT3, MX2, and CXCL10 following treatment with tyrosine kinase inhibitor (TKI). We hypothesize that inhibition of EGFR or EML4-ALK upon treatment with TKIs induces a robust IFN signaling response and an increase in T cell infiltration, thus sensitizing EGFR mutant or EML4-ALK positive lung cancer tumors to immunotherapy agents. RNAseq of EGFR mutant cell lines treated with the EGFR TKI, AZD9291 reveals broad and kinetically variable transcriptional induction of IFN pathway genes. Bioinformatic analysis demonstrates enrichment in IFNα and IFNγ pathway genes with TKI treatment. In two independent lung cancer patients, RNAseq analysis of paired biopsies taken before and after a 2-week treatment with EGFR TKI reveals a similar enrichment for IFNα and IFNγ gene sets. Furthermore, multiple bioinformatic approaches support increased T cell infiltration in the EGFR TKI-treated tumors. Likewise, crizotinib treatment (2 wks) of orthotopic murine EML4-ALK tumors in syngeneic mice induced a 3.7-fold increase in CD3+ T cells. Taken together, our data demonstrate that inhibitors of oncogenic EGFR or ALK induce an IFN signaling response in cell line models as well as patient biopsies. Ongoing studies are testing the ability of TKIs to increase the responsiveness to anti-PD1/PD-L1 therapies in EGFR and EML4-ALK-drivent lung cancers.