Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer
Triparna Sen,B. Leticia Rodriguez,Limo Chen,Carminia Maria Della Corte,Naoto Morikawa,Junya Fujimoto,Sandra Cristea,Thuyen Nguyen,Lixia Diao,Lerong Li,Youhong Fan,Yongbin Yang,Jing Wang,Bonnie S. Glisson,Ignacio I. Wistuba,Julien Sage,John V. Heymach,Don L. Gibbons,Lauren Averett Byers +18 more
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TLDR
This study shows that targeting the DNA damage response (DDR) proteins PARP and checkpoint kinase 1 (CHK1) significantly increased protein and surface expression of PD-L1 and supports a role of innate immune STING pathway in DDR-mediated antitumor immunity in SCLC.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.read more
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Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.
Charles M. Rudin,John T. Poirier,Lauren Averett Byers,Caroline Dive,Afshin Dowlati,Julie George,John V. Heymach,Jane E. Johnson,Jonathan M. Lehman,David MacPherson,Pierre P. Massion,John D. Minna,Trudy G. Oliver,Vito Quaranta,Julien Sage,Roman K. Thomas,Christopher R. Vakoc,Adi F. Gazdar +17 more
TL;DR: This Opinion, written by many leading experts in small cell lung cancer (SCLC) research, proposes a new model of SCLC subtypes defined by differential expression of four key transcription regulators that should help to focus and accelerate therapeutic research.
Journal ArticleDOI
The Cytosolic DNA-Sensing cGAS-STING Pathway in Cancer.
John Kwon,Samuel F. Bakhoum +1 more
TL;DR: mounting evidence now suggests that depending on the context, cGAS-STING signaling can also have tumor and metastasis-promoting functions, and its chronic activation can paradoxically induce an immune-suppressive tumor microenvironment.
Journal ArticleDOI
PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer
Constantia Pantelidou,Olmo Sonzogni,Mateus De Oliveria Taveira,Anita K. Mehta,Aditi Kothari,Dan Wang,Dan Wang,Tanvi Visal,Michelle K. Li,Jocelin Pinto,Jessica A. Castrillon,Emily M. Cheney,Peter Bouwman,Jos Jonkers,Sven Rottenberg,Sven Rottenberg,Jennifer L. Guerriero,Gerburg M. Wulf,Geoffrey I. Shapiro,Geoffrey I. Shapiro +19 more
TL;DR: It is demonstrated that the PARP inhibitor olaparib induces CD8+ T-cell infiltration and activation in vivo, and that CD8-cell depletion severely compromises antitumor efficacy, and provides a rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC.
Journal ArticleDOI
Small-cell lung cancer.
TL;DR: The recent introduction of immune checkpoint blockade into the treatment of patients with small-cell lung cancer (SCLC) is offering new hope, with a small subset of patients deriving prolonged benefit.
Journal ArticleDOI
Inflammatory microenvironment remodelling by tumour cells after radiotherapy.
Martin McLaughlin,Emmanuel C Patin,Malin Pedersen,Anna Wilkins,Magnus T. Dillon,Magnus T. Dillon,Alan Melcher,Alan Melcher,Kevin J. Harrington,Kevin J. Harrington +9 more
TL;DR: How radiotherapy, through its immunomodulating effects, represents a promising combination partner with ICIs and how DNA damage response inhibitors in combination with radiotherapy may be used to further augment this approach are described.
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