IL6 Signaling Enables Survival of Chromosomally Instable Cancer Cells

Chromosomal instability (CIN) is a common feature of human cancer, and resulting chromosomal abnormalities can introduce double-stranded DNA into the cytosol and activate cGAS–STING-mediated inflammatory signaling. Although this axis can promote apoptosis and immunosurveillance, CGAS and STING are rarely mutated in cancer. To study this inflammatory response in the context of CIN, Hong and colleagues induced acute or chronic CIN in triple-negative breast cancer (TNBC) cells via pharmacologic inhibition of the mitotic spindle assembly checkpoint or ectopic expression of a dominant-negative mutant form of a microtubule depolymerase, respectively. Whereas CIN activated cGAS–STING signaling, CRISPR–Cas9-mediated CGAS knockout in the context of CIN led to decreased cell viability in vitro and reduced tumor growth in vivo, suggesting that the cGAS–STING pathway promotes survival of cancer cells undergoing CIN. Functional genetic studies demonstrated that STAT3 activation was important for cell survival downstream of cGAS, as STAT3 knockout similarly sensitized TNBC cells following CIN induction. Transcriptomic analysis revealed a cGAS-dependent, CIN-induced increase in expression of the inflammatory cytokine IL6, a known activator of STAT3. In agreement with a model in which IL6 signaling promotes survival via STAT3, increasing doses of recombinant IL6 rescued cell viability following CIN induction in CGAS knockout TNBC cells, while inhibition of the IL6 receptor, via the blocking antibody tocilizumab, sensitized TNBC cells experiencing CIN. In multiple murine models, tocilizumab extended tumor-free survival and delayed progression in mice bearing CIN-high tumors. Notably, classification of breast cancer samples in The Cancer Genome Atlas based on CIN and IL6–STAT3 activity revealed that tumors with both high CIN and IL6 signaling had decreased overall survival. Moreover, these observations extended beyond breast cancer, as IL6 signaling was not only necessary for viability after induction of CIN in multiple cancer lineages but also predictive of decreased survival in patients with various tumor types. In summary, this study demonstrates the importance of cGAS–STING-mediated inflammatory signaling in enabling cancer cells to survive despite CIN.

Hong C, Schubert M, Tijhuis AE, Requesens M, Roorda M, van den Brink A, et al. cGAS–STING drives the IL-6-dependent survival of chromosomally instable cancers. Nature 2022;607:366–73.

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