Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING

Abstract

SUMMARY In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1 -mutated ( BRCA1 mut ) tumors are thus T cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine is identified as a potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1 mut cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance and tumor progression. Tumor-intrinsic STING elimination reduces neoangiogenesis, increases CD8 + T cell infiltration, and reverts therapeutic resistance to dual immune checkpoint blockade (ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with ICB and/or poly(ADP-ribose) polymerase (PARP) inhibitors to control the outgrowth of Trp53 −/− Brca1 −/− but not Brca1 +/+ ovarian tumors in vivo , offering rational combinatorial therapies for HRD cancers.

Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer

“…Moreover, tumors derived from a Brca1 -deficient cancer that progressed on treatment lose their ability to induce senescence and SASP upon cisplatin treatment, leading to resistance to cisplatin in combination with ICB. Interestingly, the increased propensity of Brca1 -deficient tumors to undergo senescence and/or activate the cGas/STING pathway appears to extend to other agents, as Brca1 -deficient models of breast and ovarian cancer treated with PARP inhibitors or, as shown here, taxol show similar behaviors ( 70 – 74 ). As such, senescence induction may underlie the improved response of HR-deficient tumors to genome destabilizing therapies in the clinic.…”

CCL5 as a Prognostic Marker for Survival and an Indicator for Immune Checkpoint Therapies in Small Cell Lung Cancer

“…Different conclusions have been drawn about the role of CCL5 in tumors. Some studies accounted CCL5 for the promotion of tumor development by suppressing the immune response ( 19 ), whereas some studies regarded CCL5 as a tumor protective factor associated with high CD8+ T cell infiltration ( 20 , 21 ). In this study, we first evaluated the relationship between CCL5 and survival in patients with SCLC.…”

DNA Damage Response and Cancer Metastasis: Clinical Implications and Therapeutic Opportunities

“…Studies have shown that phosphorylation of H2AX at S139, known as γH2AX, triggered by active ATM kinase during double stranded DNA breaks can interact with HIF-1α to maintain its stability and nuclear accumulation, thereby facilitating HIF-1α/hypoxia signaling activation and predicting metastatic outcome (57). Homologous recombination deficiency such as BRCA1 loss can lead to upregulation of pro-angiogenic factors such as VEGF through transcriptional reprogramming in tumor cells via stimulator of interferon genes (STING) (58). Third, DDR defect and related DNA damages, on the other hand, may inhibit tumor metastatic potential by recruiting tumor infiltrating lymphocytes (TIL) to the microenvironment.…”