79P - Targeting galectin-9 in BRCA mutant breast cancer

Background

BRCA-mutant breast cancer (BC) are characterized by their high immunogenicity due to the dysregulation of the homologous DNA repair mechanism and genomic instability. Aberrant DNA instigates immune signaling through the cGAS/STING pathway which enhances hosts' immune response to fight against neoplastic cells. However, chronic activation of the STING pathway can have a double-edged effect: while it induces type I interferons that suppress tumor growth, it also promotes the expression of Galectin-9 (Gal-9) which is immunosuppressive in the tumor microenvironment (TME). Our study aims to investigate how treatment with Olaparib (an established treatment for BRCA mutant BC) would lead to the overexpression of Gal-9 and as a potential target for treatment.

Methods

Part 1: We explored the TCGA breast cancer dataset and studied the enrichment scores associated with the cGAS-STING pathway in TNBC samples. Correlation analysis on LGALS9 expression with respect to immune cells in tumor microenvironment was performed. Part 2: BRCA-mutant breast cancer cell lines MDA-MB-436 and HCC1937 were treated with Olaparib for 3 days at different concentrations. Gal-9 and cGAS/STING pathway expression were measured by qPCR and immunoblot.

Results

Significantly elevated expression of LGALS9, cGAS, and IFNB1 was observed in TNBC. The gene signature associated with the cGAS-STING pathway also demonstrated higher enrichment scores. Correlation analysis using the CIBERSORT algorithm illustrated that LGALS9 expression positively correlated with the infiltration of T cell subsets (CD4+, CD8+, and regulatory T cells) as well as M1 macrophages, suggesting a potential role for Gal-9 in shaping the TME. Olaparib treatment in BRCA mut BC cell lines led to an increase in Gal-9 expression positively correlating with Olaparib concentration. The addition of H151, a STING inhibitor, suppressed the activation of the cGAS/STING pathway and Gal-9 expression indicating that Gal-9 expression is dependent on STING activation.

Conclusions

BRCA mutant BC treated with PARPi demonstrated activation of cGAS/STING pathway and Gal-9 overexpression. Further animal work will be conducted to assess the feasibility of combining Olaparib with anti-Gal-9 antibodies as a potential treatment strategy and its associated impact on TME.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.