Polymerase θ inhibition steps on the cGAS pedal

In the current issue of the JCI, Oh and Wang, et al. report findings that reveal the impact of Pol θ inhibition on immune activation (Figure 1) (14). Their study focuses on pancreatic ductal adenocarcinoma (PDAC), motivated by the observations that nearly a quarter of PDAC cases are associated with HR-associated gene alterations and that POLQ overexpression correlates with worse prognosis in two independent cohorts of PDAC patients. Pol θ was a synthetically lethal target in patient-derived and murine PDAC models in combination with mutations in either of the HR genes BRCA1 or BRCA2, or in ATM, which is an upstream kinase that responds to DSBs and activates signaling events required for HR repair. Genetic knockdown of POLQ and treatment with Pol θ inhibitors resulted in broad growth inhibition and accumulation of unrepaired DNA damage in HR-deficient PDAC models, relative to PDAC models that lacked HR-associated gene mutations. Furthermore, the authors observed additive — and possibly synergistic — effects when combining Pol θ inhibitors with PARP inhibitors in HR-deficient models. These observations validate Pol θ as a promising therapeutic target in HR-deficient PDAC (14).

Pol θ inhibition stimulates cGAS/STING to promote T cell-directed anti-tumoFigure 1

Pol θ inhibition stimulates cGAS/STING to promote T cell-directed anti-tumor immunity. BRCA2-/- PDAC tumor cells compensate for the loss of HR by upregulating Pol θ, which mediates TMEJ and is essential for repairing DSBs. Inhibition of Pol θ results in accumulation of cGAS-positive micronuclei and STING activation. The cGAS/STING pathway activates TBK1 and IRF3 via phosphorylation, initiating Type I IFN production and release. Subsequent increases in CD4+ and CD8+ T cell infiltration with decreasing immunosuppressive M2-like TAMs result in suppression of tumor growth.

Oh, Wang, and authors went on to demonstrate that Pol θ inhibition in HR-deficient (i.e., BRCA1, BRCA2, and ATM mutant) PDAC stimulated the accumulation of cyclic GMP-AMP synthase–positive (cGAS-positive) micronuclei. cGAS and its downstream partner stimulator of IFN genes (STING) constitute a cytosolic DNA sensing pathway that activates the innate immune system through transcriptional activation of IFN-stimulated genes (14, 15). While the innate immune system primarily serves as a defense against exogenous DNA during viral or bacterial infection, it also senses damaged DNA within the cell’s cytosol. Hence, the cGAS/STING pathway functions in tumor surveillance and in the immunological response to cancer therapy by responding to an accumulation of unrepaired DNA.

The authors also showed that Pol θ inhibition followed by cGAS/STING activation had therapeutically relevant immunological consequences. Through in vivo analysis of a Brca2-deficient murine PDAC model, the authors demonstrated that Pol θ inhibition increased intratumoral CD4+ and CD8+ T cell infiltration, while tumor-associated macrophages (TAMs) decreased, primarily due to a decrease in immunosuppressive M2-like TAMs. These effects were dependent on STING, as knockdown of STING diminished these effects, despite Pol θ targeting, resulting in partial restoration of tumor growth (14). These results are consistent with a recently published complementary study by Patterson-Fortin et al., which demonstrated that Pol θ inhibition increased micronuclei formation, cGAS/STING pathway activation, and CD8+ T cell influx (16). Additionally, the Patterson-Fortin et al. study observed an upregulation of PD-L1 expression and saw additive effects of Pol θ inhibition with anti-PD-1 therapy in HR-deficient triple–negative breast cancer and PDAC models (16).

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