TY - JOUR
T1 - Topoisomerase I poison-triggered immune gene activation is markedly reduced in human small-cell lung cancers by impairment of the cGAS/STING pathway
AU - Marinello, Jessica
AU - Arleo, Andrea
AU - Russo, Marco
AU - Delcuratolo, Maria
AU - Ciccarelli, Francesca
AU - Pommier, Yves
AU - Capranico, Giovanni
N1 - Funding Information:
The results shown here regarding lung adenocarcinoma and lung squamous cell carcinoma are based upon data generated by the TCGA Research Network (https://www.cancer.gov/tcga). We also acknowledge the EMBL-EGA Data Archive and the Department of Translational Genomics of the University of Cologne for sharing datasets EGAD00001001244 and EGAD00001001431 regarding RNA-seq data of small-cell lung cancer samples.
Funding Information:
The research has received funding from AIRC under IG 2019 - ID. 23032 project - P.I. Capranico Giovanni, from Ministry of University and Research under PRIN 2017 - KSZZJW_004 and from CARISBO (Ricerca Medica e Alta Tecnologia 2021), P.I. Marinello Jessica, and from University of Bologna PhD programme (fellowship to Andrea Arleo). Yves Pommier is supported by the Intramural Program, Center for Cancer Research of the NCI NIH, Z01-BC-006161.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/10/19
Y1 - 2022/10/19
N2 - BACKGROUND: Current immunotherapy strategies have contrasting clinical results in human lung cancer patients as small-cell lung cancers (SCLC) often show features of immunological cold tumours. Topoisomerase 1 (TOP1) poisons are effective antitumor drugs with good efficacy against lung cancers.METHODS: We used molecular, genetic and bioinformatic approaches to determine the mechanism of micronuclei formation induced by two TOP1 poisons in different human cancer cells, including SCLC cell lines.RESULTS: TOP1 poisons stimulate similar levels of micronuclei in all tested cell lines but downstream effects can vary markedly. TOP1 poisons increase micronuclei levels with a mechanism involving R-loops as overexpression of RNaseH1 markedly reduces or abolishes both H2AX phosphorylation and micronuclei formation. TOP1 poison-induced micronuclei activate the cGAS/STING pathway leading to increased expression of immune genes in HeLa cells, but not in human SCLC cell lines, mainly due to lack of STING and/or cGAS expression. Moreover, the expression of STING and antigen-presenting machinery genes is generally downregulated in patient tumours of human lung cancer datasets.CONCLUSIONS: Altogether, our data reveal an immune signalling mechanism activated by TOP1 poisons, which is often impaired in human SCLC tumours.
AB - BACKGROUND: Current immunotherapy strategies have contrasting clinical results in human lung cancer patients as small-cell lung cancers (SCLC) often show features of immunological cold tumours. Topoisomerase 1 (TOP1) poisons are effective antitumor drugs with good efficacy against lung cancers.METHODS: We used molecular, genetic and bioinformatic approaches to determine the mechanism of micronuclei formation induced by two TOP1 poisons in different human cancer cells, including SCLC cell lines.RESULTS: TOP1 poisons stimulate similar levels of micronuclei in all tested cell lines but downstream effects can vary markedly. TOP1 poisons increase micronuclei levels with a mechanism involving R-loops as overexpression of RNaseH1 markedly reduces or abolishes both H2AX phosphorylation and micronuclei formation. TOP1 poison-induced micronuclei activate the cGAS/STING pathway leading to increased expression of immune genes in HeLa cells, but not in human SCLC cell lines, mainly due to lack of STING and/or cGAS expression. Moreover, the expression of STING and antigen-presenting machinery genes is generally downregulated in patient tumours of human lung cancer datasets.CONCLUSIONS: Altogether, our data reveal an immune signalling mechanism activated by TOP1 poisons, which is often impaired in human SCLC tumours.
UR - http://www.scopus.com/inward/record.url?scp=85133596903&partnerID=8YFLogxK
U2 - 10.1038/s41416-022-01894-4
DO - 10.1038/s41416-022-01894-4
M3 - Article
C2 - 35794238
SN - 1532-1827
VL - 127
SP - 1214
EP - 1225
JO - British journal of cancer
JF - British journal of cancer
IS - 7
ER -