Abstract
Background: Triple-negative breast cancer (TNBC) is highly drug resistant and heterogenous; however, its relatively high immunogenicity renders immunotherapies a promising therapeutic strategy. Our group has previously shown that RASAL2, a RAS GTPase-activating protein (RAS-GAP), is specifically overexpressed in aggressive TNBC patients and has been implicated in mediating chemoresistance. This study aimed to decipher the mechanistic roleof RASAL2 in TNBC progression from an immunological perspective.
Methods: A panel of isogenic TNBC cell lines (MDA-MB-468, MDA-MB-231 and HCC1937) with differential RASAL2 expression levels were generated, and their cell surface major histocompatibility complex I (MHC-I) expression levels were characterised by flow cytometry and immunofluorescence imaging. 3D live cell imaging was then employed to follow the effect of co-culturing Jurkat T cells on MDA-MB-468 cells. The co-cultured CD8+ T-cells were also analysed for their activation status determined by CD69 expression.
Results: High RASAL2 levels induced a more immunologically ‘invisible’ phenotype, marked by downregulation of MHC-I, in TNBC cells. RASAL2 overexpression conferred resistance to immune-mediated killing and reduced CD8+ T-cell activation as determined by surface CD69 levels, suggesting impaired recognition of TNBC cells by CD8+ T-cells.
Conclusion: This study suggests a novel immunomodulatory effect of the RAS-GAP RASAL2 in TNBC. Thus, RASAL2 is a promising candidate biomarker to inform clinical decisions and improve immunotherapy responses in TNBC.
| Date of Award | 9 Dec 2025 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Siang Boon Koh (Supervisor) & Nobue Itasaki (Supervisor) |
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