ESTRO 2020 Abstract book
S144 ESTRO 2020
SP-0258 Potentiation of anti-tumor immune effects by PARP Inhibitors R. Chabanon 1 , G. Muirhead 2 , D. Krastev 2 , J. Adam 3 , M. Garrido 4 , D. Morel 1 , N. Dorvault 1 , S. Pettitt 2 , A.N.J. Tutt 5 , A. Marabelle 6 , J.C. Soria 6 , C.J. Lord 7 , S. Postel-Vinay 8 1 gustave Roussy, U981 Inserm - Atip Avenir, Villejuif, France ; 2 the Institute Of Cancer Research, Cruk Gene Function Laboratory, London, United Kingdom ; 3 gustave Roussy, Pathology Department, Villejuif, France ; 4 gustave Roussy, U981 Inserm, Villejuif, France ; 5 the Institute Of Cancer Research, The Breast Cancer Now Research Unit, London, United Kingdom ; 6 gustave Roussy, Drug Development Department, Villejuif, France ; 7 the Institute Of Cancer Research, The Breast Cancer Now Research Unit And Cruk Gene Function Laboratory, London, United Kingdom ; 8 gustave-Roussy, Drug Development Department - Inserm U981, Villejuif, France Abstract text Background and overview of the presentation : Poly(ADP- ribose) polymerase inhibitors (PARPi) have shown clinical or preclinical anti-tumour efficacy in DNA damage response (DDR)-deficient cancers such as BRCA1 -mutant ovarian, triple-negative breast (TNBC) and pancreatic cancer, as well as Excision Repair Cross Complementation 1 ( ERCC1 )-defective non-small cell lung cancer (NSCLC). Various interplays have been described between PARPi and the anti-cancer immune response, notably through the cytosolic DNA sensing cGAS/STING pathway which stimulates anti-cancer immunity by activating innate immune responses. In this session, our original work performed on the interplay between PARPi and anti-cancer immune response will be presented (see details below). This will be put in the context of available literature data and work published by other groups, as well as recent results from clinical trials evaluating the combination of PARPi with immune checkpoint blockers. Material and Methods: We took advantage of a unique combination of isogenic models of ERCC1 -deficient NSCLC and BRCA1 -mutant TNBC to evaluate the effects of PARPi on tumour cell-intrinsic immune phenotypes. We used RNAseq to identify cell-autonomous transcriptional changes associated with loss of ERCC1 and PARPi exposure. We further performed high-content immunofluorescent screening to assess the presence of cytosolic DNA in cells exposed to several clinical PARPi, and monitored cGAS/STING pathway activation via detection of cGAS cytoplasmic re-localization, TBK1 phosphorylation, and secretion of chemotactic chemokines. PD-L1 modulation on PARPi exposure was assessed by FACS. To explore the clinical relevance of our preclinical finding, we using resected NSCLC series to assess the correlation between ERCC1 expression and tumour infiltrating lymphocytes. Results: We found that exposure to PARPi selectively triggers cGAS/STING pathway activation and type I IFN signalling in ERCC1 or BRCA1-defective cells. Mechanistically, we established that PARPi induce cell cycle-dependent formation of cytosolic chromatin fragments (CCF) in ERCC1 -defective NSCLC and BRCA1 - mutant TNBC cells. We observed that CCFs are detected by cGAS, which activates the cGAS/STING pathway and type I interferon response, resulting in the secretion of chemotactic chemokines such as CCL5 in a cell- autonomous fashion. Importantly, re-expression of ERCC1 or reversion of BRCA1 mutation in ERCC1 -KO or BRCA1 - mutant cells, respectively, suppresses these effects, thereby supporting the pivotal role of these genetic
Symposium: Emerging links between radiation-induced anti-tumor immune effects and DNA damage repair signaling
SP-0256 Pathways linking DNA damage repair to adaptive anti-tumor immunity C. Vanpouille 1 1 Weill Cornell Medicine, Department of Radiation Oncology, New York, USA Abstract text Alterations of the DNA damage repair (DDR) response in cancer cells often result in genomic instability that can be characterized by accumulation of mutations and complex genomic rearrangements. It is well recognized that increase mutations drive carcinogenesis, however, genomic instability can also lead to the release of DNA into the cytoplasm, a consequence of a dysregulated DDR response. Mislocalized DNA is known to jumpstart innate and adaptive responses by eliciting viral defense mechanisms among which the activation of the cGAS (cyclic GMP-AMP synthase) and STING (stimulator of IFN genes) pathway. As a consequence, to escape immune recognition, cancer cells have developed multiple strategies; among which the upregulation of the DNA exonuclease 3’-repair exonuclease 1 (TREX1). TREX1 has been demonstrated to dictate the immune fate of an irradiated cancer cell by degrading cytosolic DNA prior its recognition by the nucleic acid sensor cGAS. Importantly, TREX1 has also been shown to stabilize poly(ADP-ribose) polymerase 1 (PARP1) levels during the DNA damage response, thus suggesting a link between the DNA damage repair machinery and anti-tumor immunity. As a consequence, a better understanding of the underlying mechanisms that link DNA damage repair and anti-tumor immunity is critical to improve the combination of radiation therapy with immunotherapeutic agents. SP-0257 Innate immune responses caused by radiation-induced micronuclei S. Harding 1 1 University Health Network, Princess Margaret Cancer Centre, Toronto, Canada Abstract text Radiotherapy remains a pillar of cancer medicine but the full range of cellular responses to these treatments have not yet been fully realized. In addition to cell cycle checkpoints and activation of DNA repair, radiation can drive induction of multiple cytokines and chemokines that initiate changes in the tumour microenvironment. Such changes have the potential to both enhance and suppress immune-mediated responses and has important implications for emerging combination modalities that include immunotherapy. Furthermore, these chronic inflammatory signals generated by RT may also influence radiotherapy-driven toxicity. We have identified connections between cell cycle checkpoints and inflammatory signaling that are tied to viral responses proteins called pattern recognition receptors. The goal of our studies is to understand how such radiotherapy-driven inflammatory signaling can be harnessed to improve treatment and suppress normal tissue toxicity.
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