A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer

Abstract

Tyrosine kinase inhibitors (TKIs) targeting EGFR-mutant lung cancers promote a range of tumor regression responses to yield variable residual disease, a likely incubator for acquired resistance. Herein, rapid transcriptional responses induced by TKIs early in treatment that associate with the range of patient responses were explored. RNAseq was performed on EGFR mutant cell lines treated in vitro with osimertinib and on tumor biopsies of eight EGFR mutant lung cancer patients before and after 2 weeks of TKI treatment. Data were evaluated for gene expression programs altered upon TKI treatment. Chemokine and cytokine expression were measured by ELISA and quantitative RT-PCR. IκB Kinase (IKK) and JAK-STAT pathway dependence was tested with pharmacologic and molecular inhibitors. Tumor sections were stained for the T-cell marker CD3. Osimertinib stimulated dynamic, yet wide-ranging interferon (IFN) program regulation in EGFR mutant cell lines. IL6 and CXCL10 induction varied markedly among the EGFR mutant cell lines and was sensitive to IKK and JAK-STAT inhibitors. Analysis of matched patient biopsy pairs revealed marked, yet varied enrichment of IFN transcriptional programs, effector immune cell signatures and T-cell content in treated tumors that positively correlated with time to progression in the patients. EGFR-specific TKIs induce wide-ranging IFN response program activation originating within the cancer cell. The strong association of IFN program induction and duration of clinical response indicates that the TKI-induced IFN program instructs variable recruitment and participation of immune cells in the overall therapeutic response.

Adaptive immunity is required for durable responses to alectinib in murine models of EML4-ALK lung cancer

“…Thus, understanding the biological underpinnings for variation in DepOR and time to progression may inform rational strategies for enhancing the efficacy of oncogenetargeted agents through novel drug combinations. Our recent published studies demonstrate that EGFRtargeted inhibitors induce an interferon (IFN) response program that varies markedly between distinct EGFR mutant lung cancer cell lines and positively associates with the duration of therapeutic response in EGFR-mutant lung cancer patients (7). In fact, there is a growing literature supporting the role of host immune cells in overall therapeutic response to precision oncology agents and cytotoxic drugs (8)(9)(10)(11).…”

Role of Immune Checkpoint Inhibitor Therapy in Advanced EGFR-Mutant Non-Small Cell Lung Cancer

“…Gurule et al. performed RNA sequencing of patient tumors before and 2 weeks after TKI treatment and demonstrated induction of an interferon response program ( 71 ). Interestingly, higher enrichment of interferon gamma (IFNγ) was correlated with longer time to progression.…”

“…A number of trials have evaluated combination ICI therapy and EGFR-targeted therapy in the second-line and beyond. These studies were predicated on pre-clinical studies that suggested added benefit to the combined approach in animal models (68)(69)(70)(71). However, results have mostly been disappointing and in many cases demonstrated increased and severe toxicities.…”

“…Multiple lines of pre-clinical evidence suggested synergy between EGFR TKI inhibition and ICI therapy. In pre-clinical studies, EGFR inhibition enhanced antigen presentation to T-cells, stimulated immunogenic apoptosis of tumor cells, boosted T-cell chemoattractants, and stimulated MHC-1 upregulation, all of which are predicted to enhance the anti-tumor immune response (68)(69)(70)(71). Despite this, early clinical studies demonstrated that preclinical studies would not translate in a straightforward manner.…”

“…Also of interest, the PD-L1 high tumors had increased FOXP3+ and CD73 TIL density, suggesting that regulatory T-cell (Treg) and CD73 axis activation may contribute to ICI treatment failure. (71). Interestingly, higher enrichment of interferon gamma (IFNg) was correlated with longer time to progression.…”