Topoisomerase I poison-triggered immune gene activation is markedly reduced in human small-cell lung cancers by impairment of the cGAS/STING pathway

Abstract

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.

Releasable hydrogel microsphere-drug conjugates as generic prodrugs for long-acting intra-tumoral therapy

“…Likely, because TOP1i have significant immune modulatory effects (46)(47)(48)(49), future studies in immunocompetent mice may uncover aspects of long-acting IT delivery of the agents that better reflect expectations in patients.…”

Anlotinib enhances the antitumor immunity of radiotherapy by activating cGAS/STING in non-small cell lung cancer

“…In the present study, we found that triple therapy further activated cGAS/STING signaling, increased CD8 + T cell proliferation and enhanced the immune memory activation that facilitated tumor regression and durable control. A previous report demonstrates that STING downregulation is generally observed in human lung cancer subtypes, including small-cell lung cancer, large-cell neuroendocrine lung cancer, LUAD and LUSC, in comparison to normal lung tissues [ 46 ]. To further confirm the effect of STING expression on patient survival, we analyzed TCGA dataset of lung cancer.…”

Nanoparticle‐Mediated STING Activation for Cancer Immunotherapy

“…[ 62 ] ATR and topoisomerase 1 (TOP1) inhibitor activates the STING pathway by micronuclei. [ 63 ] RNA polymerase I (POL I) CX‐5461 is one of the most promising POL I inhibitors being studied at present. Treatment with CX‐5461 can induce rapid accumulation of cytosolic DNA, leading to the up‐regulated transcription of STING.…”