The clinical and molecular significance associated with STING signaling in breast cancer

Eileen E. Parkes; Matthew P. Humphries; Elaine Gilmore; Fatima A. Sidi; Victoria Bingham; Su M. Phyu; Stephanie Craig; Catherine Graham; Joseph Miller; Daryl Griffin; Manuel Salto-Tellez; Stephen  Madden; Richard D. Kennedy; Samuel F Bakhoum; Stephen McQuaid; Niamh E Buckley

doi:10.1038/s41523-021-00283-z

The clinical and molecular significance associated with STING signaling in breast cancer

Eileen E. Parkes, Matthew P. Humphries, Elaine Gilmore, Fatima A. Sidi, Victoria Bingham, Su M. Phyu, Stephanie Craig, Catherine Graham, Joseph Miller, Daryl Griffin, Manuel Salto-Tellez, Stephen Madden, Richard D. Kennedy, Samuel F Bakhoum, Stephen McQuaid, Niamh E Buckley^*

^*Corresponding author for this work

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Abstract

STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. 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 in estrogen receptor-positive (ER+) and ER- breast cancer, we identify perinuclear-localized expression of STING (pnSTING) in ER+ cases 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”-polarized macrophages. In ER- disease, pnSTING does not appear to have a significant prognostic role with STING uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression is predictive of poor prognosis in independent ER+ datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup.

Original language	English
Article number	81
Number of pages	11
Journal	npj Breast Cancer
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41523-021-00283-z https://doi.org/10.1038/s41523-021-00283-z
Publication status	Published - 25 Jun 2021

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The clinical and molecular significance associated with STING signaling in breast cancer
Copyright 2021 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 7.26 MBLicence: CC BY

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Parkes, E. E., Humphries, M. P., Gilmore, E., Sidi, F. A., Bingham, V., Phyu, S. M., Craig, S., Graham, C., Miller, J., Griffin, D., Salto-Tellez, M., Madden, S., Kennedy, R. D., Bakhoum, S. F., McQuaid, S., & Buckley, N. E. (2021). The clinical and molecular significance associated with STING signaling in breast cancer. npj Breast Cancer, 7(1), [81]. https://doi.org/10.1038/s41523-021-00283-z, https://doi.org/10.1038/s41523-021-00283-z

Parkes, Eileen E. ; Humphries, Matthew P. ; Gilmore, Elaine ; Sidi, Fatima A. ; Bingham, Victoria ; Phyu, Su M. ; Craig, Stephanie ; Graham, Catherine ; Miller, Joseph ; Griffin, Daryl ; Salto-Tellez, Manuel ; Madden, Stephen ; Kennedy, Richard D. ; Bakhoum, Samuel F ; McQuaid, Stephen ; Buckley, Niamh E. / The clinical and molecular significance associated with STING signaling in breast cancer. In: npj Breast Cancer. 2021 ; Vol. 7, No. 1.

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title = "The clinical and molecular significance associated with STING signaling in breast cancer",

abstract = "STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. 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 in estrogen receptor-positive (ER+) and ER- breast cancer, we identify perinuclear-localized expression of STING (pnSTING) in ER+ cases 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”-polarized macrophages. In ER- disease, pnSTING does not appear to have a significant prognostic role with STING uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression is predictive of poor prognosis in independent ER+ datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup.",

author = "Parkes, {Eileen E.} and Humphries, {Matthew P.} and Elaine Gilmore and Sidi, {Fatima A.} and Victoria Bingham and Phyu, {Su M.} and Stephanie Craig and Catherine Graham and Joseph Miller and Daryl Griffin and Manuel Salto-Tellez and Stephen Madden and Kennedy, {Richard D.} and Bakhoum, {Samuel F} and Stephen McQuaid and Buckley, {Niamh E}",

year = "2021",

month = jun,

day = "25",

doi = "10.1038/s41523-021-00283-z",

language = "English",

volume = "7",

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Parkes, EE, Humphries, MP , Gilmore, E, Sidi, FA, Bingham, V, Phyu, SM, Craig, S, Graham, C, Miller, J, Griffin, D , Salto-Tellez, M, Madden, S, Kennedy, RD, Bakhoum, SF, McQuaid, S & Buckley, NE 2021, 'The clinical and molecular significance associated with STING signaling in breast cancer', npj Breast Cancer, vol. 7, no. 1, 81. https://doi.org/10.1038/s41523-021-00283-z, https://doi.org/10.1038/s41523-021-00283-z

The clinical and molecular significance associated with STING signaling in breast cancer. / Parkes, Eileen E.; Humphries, Matthew P.; Gilmore, Elaine; Sidi, Fatima A.; Bingham, Victoria; Phyu, Su M.; Craig, Stephanie; Graham, Catherine; Miller, Joseph; Griffin, Daryl ; Salto-Tellez, Manuel; Madden, Stephen ; Kennedy, Richard D.; Bakhoum, Samuel F; McQuaid, Stephen; Buckley, Niamh E.

In: npj Breast Cancer, Vol. 7, No. 1, 81, 25.06.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - The clinical and molecular significance associated with STING signaling in breast cancer

AU - Parkes, Eileen E.

AU - Humphries, Matthew P.

AU - Gilmore, Elaine

AU - Sidi, Fatima A.

AU - Bingham, Victoria

AU - Phyu, Su M.

AU - Craig, Stephanie

AU - Graham, Catherine

AU - Miller, Joseph

AU - Griffin, Daryl

AU - Salto-Tellez, Manuel

AU - Madden, Stephen

AU - Kennedy, Richard D.

AU - Bakhoum, Samuel F

AU - McQuaid, Stephen

AU - Buckley, Niamh E

PY - 2021/6/25

Y1 - 2021/6/25

N2 - STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. 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 in estrogen receptor-positive (ER+) and ER- breast cancer, we identify perinuclear-localized expression of STING (pnSTING) in ER+ cases 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”-polarized macrophages. In ER- disease, pnSTING does not appear to have a significant prognostic role with STING uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression is predictive of poor prognosis in independent ER+ datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup.

AB - STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. 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 in estrogen receptor-positive (ER+) and ER- breast cancer, we identify perinuclear-localized expression of STING (pnSTING) in ER+ cases 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”-polarized macrophages. In ER- disease, pnSTING does not appear to have a significant prognostic role with STING uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression is predictive of poor prognosis in independent ER+ datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup.

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M3 - Article

VL - 7

JO - npj Breast Cancer

JF - npj Breast Cancer

SN - 2374-4677

IS - 1

M1 - 81

ER -

The clinical and molecular significance associated with STING signaling in breast cancer

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