The clinical and molecular significance associated with STING signaling in estrogen receptor-positive early breast cancer

Parkes, E. E.; Humphries, M. P.; Gilmore, E.; Sidi, F. A.; Bingham, V.; Phyu, S. M.; Craig, S. G.; Graham, C.; Miller, J.; Griffin, D.; Kennedy, R. D.; Bakhoum, S. F.; McQuaid, S.; Salto-Tellez, M.; Buckley, N. E.

doi:10.1101/2020.07.23.217398

bioRxiv · 10.1101/2020.07.23.217398

The clinical and molecular significance associated with STING signaling in estrogen receptor-positive early breast cancer

Parkes, E. E.·Humphries, M. P.·Gilmore, E.·Sidi, F. A.·Bingham, V.·Phyu, S. M.·Craig, S. G.·Graham, C.·Miller, J.·Griffin, D.·Kennedy, R. D.·Bakhoum, S. F.·McQuaid, S.·Salto-Tellez, M.·Buckley, N. E.

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Abstract

STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. Conversely, STING signaling can promote tumor invasion and metastasis. Currently, there is no robust method of measuring STING activation in cancer. Here, we describe an immunohistochemistry-based assay with digital pathology assessment of STING in tumor cells. Using this novel approach, we identify perinuclear-localized expression of STING (pnSTING) in estrogen receptor-positive (ER+) breast cancer as an independent predictor of good prognosis, associated with immune cell infiltration and upregulation of immune checkpoints. Tumors with low pnSTING are immunosuppressed with increased infiltration of "M2" -polarised macrophages. In ER-disease, pnSTING does not have a significant prognostic role, and STING appears to be uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression in ER+ disease is predictive of poor prognosis in independent datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup.

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Parkes, E. E., Humphries, M. P., Gilmore, E., Sidi, F. A., Bingham, V., Phyu, S. M., Craig, S. G., Graham, C., Miller, J., Griffin, D., Kennedy, R. D., Bakhoum, S. F., McQuaid, S., Salto-Tellez, M., Buckley, N. E.. 2020-07-24. The clinical and molecular significance associated with STING signaling in estrogen receptor-positive early breast cancer. https://doi.org/10.1101/2020.07.23.217398

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