The Search for Genomic Biomarkers of Response to Immunotherapy in Ovarian Cancer

Abstract

Immune checkpoint blockade has been ineffective in ovarian cancer, and there is an ongoing effort to identify biomarkers of therapeutic benefit. Despite promising preclinical data, a substudy of the IMagyn050 trial found that patients with homologous recombination deficient tumors did not have improved progression-free survival with the addition of the PD-L1 inhibitor atezolizumab. See related article by Landen et al., p. 1698.

Figure 1:

High grade serous ovarian cancer is a chromosomally unstable tumor type characterized by ongoing copy number alterations. Missegregation of chromosomes in mitosis can lead to the formation of micronuclei (MN). Loss of chromosome 6p can lead to loss of MHC I molecules facilitating T-cell immune evasion (right panel). Rupture of MN results in activation of cGAS, which results in the generation of the second messenger cGAMP. Binding of cGAMP results in a STING conformational change facilitating TBK1 mediated phosphorylation of IRF3 and activation of type 1 interferon response genes. Chronic cGAS/STING signaling in chromosomally unstable tumors is thought to facilitate immune evasion through the action of act an immunosuppressive non-canonical NF-kB pathway. (Figure partly created with BioRender.com.)