Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer
Top Cited Papers
- 1 May 2019
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 9 (5), 646-661
- https://doi.org/10.1158/2159-8290.cd-18-1020
Abstract
Despite recent advances in the use of immunotherapy, only a minority of small cell lung cancer (SCLC) patients respond to immune checkpoint blockade (ICB). Here, we show that targeting DNA damage response (DDR) proteins, poly ADP-ribose polymerase (PARP) and checkpoint kinase 1 (CHK1) significantly increased protein and surface expression of PD-L1. PARP or CHK1 inhibition remarkably potentiated the anti-tumor effect of PD-L1 blockade and augmented cytotoxic T-cell infiltration in multiple immunocompetent SCLC in vivo models. CD8 depletion reversed the anti-tumor effect demonstrating the role of CD8+ T-cells in combined DDR-PD-L1 blockade in SCLC. We further demonstrate that DDR inhibition activated the STING/TBK1/IRF3 innate immune pathway, leading to increased levels of chemokines such as CXCL10 and CCL5 that induced activation and function of cytotoxic T-lymphocytes. Knockdown of cGAS and STING successfully reversed the anti-tumor effect of combined inhibition DDR and PD-L1. Our results define previously unrecognized innate immune pathway-mediated immunomodulatory functions of DDR proteins and provide a rationale for combining PARP/CHK1 inhibitors and immunotherapies in SCLC.Keywords
Other Versions
Funding Information
- HHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI) (U01-CA213273)
- HHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI) (U01-CA213273)
- HHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI) (U01-CA213273)
- HHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI) (R01-CA207295)
- HHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI) (P30-CA016672)
- HHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI) (P50-CA070907)
- HHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI) (P50-CA070907)
- Lung Cancer Research FoundationLung Cancer Research Foundation (LCRF)
This publication has 44 references indexed in Scilit:
- A Drug Repositioning Approach Identifies Tricyclic Antidepressants as Inhibitors of Small Cell Lung Cancer and Other Neuroendocrine TumorsCancer Discovery, 2013
- Proteomic Markers of DNA Repair and PI3K Pathway Activation Predict Response to the PARP Inhibitor BMN 673 in Small Cell Lung CancerClinical Cancer Research, 2013
- Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon PathwayScience, 2013
- Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1Cancer Discovery, 2012
- Small cell lung cancer tumour cells induce regulatory T lymphocytes, and patient survival correlates negatively with FOXP3+ cells in tumour infiltrateInternational Journal of Cancer, 2012
- The DNA Damage Response Induces IFNPublished by The American Association of Immunologists ,2011
- STING is a direct innate immune sensor of cyclic di-GMPNature, 2011
- CXCR3 in T cell functionExperimental Cell Research, 2011
- Loss of p130 Accelerates Tumor Development in a Mouse Model for Human Small-Cell Lung CarcinomaCancer Research, 2010
- STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunityNature, 2009