Compartment-specific tumor-infiltrating immune cells and prognosis in breast cancer

Aaron J. Bernstein; Renske Keeman; Amber N. Hurson; Fiona M. Blows; Manjeet K. Bolla; Jodi L. Miller; Roger L. Milne; Hugo Horlings; Alexandra J. van den Broek; Clara Bodelon; James M. Hodge; Alpa V. Patel; Lauren R. Teras; Federico Canzian; Rudolf Kaaks; Hermann Brenner; Ben Schöttker; Sabine Behrens; Jenny Chang-Claude; Tabea Maurer; Nadia Obi; Fergus J. Couch; H. Raza Ali; Carlos Caldas; Irene Andrulis; Gord Glendon; Anna Marie Mulligan; Wilma Mesker; Agnes Jager; Annette Heemskerk-Gerritsen; Peter Devilee; Scott M. Lawrence; Jolanta Lissowska; Karun Mutreja; Thomas Ahearn; Stephen Chanock; Maire A. Duggan; Diana Eccles; J. Louise Jones; Will Tapper; Antoinette Hollestelle; Maartje Hooning; John Martens; Carolien H.M. van Deurzen; Angela Cox; Simon S. Cross; Mikael Hartman; Jingmei Li; Thomas C. Putti; Ute Hamann; Muhammad Rashid; Ania Jakubowska; Nicki Camp; Melissa H. Cessna; Amy Berrington de Gonzalez; Katarzyna Bialkowska; Jacek Gronwald; Jan Lubiński; Siddhartha Yadav; Pietro Lio; Douglas F. Easton; Mustapha Abubakar; Montse Garcia-Closas; Paul D.P. Pharoah; Marjanka K. Schmidt

doi:10.1016/j.isci.2026.114759

Compartment-specific tumor-infiltrating immune cells and prognosis in breast cancer

Aaron J. Bernstein
, Renske Keeman
, Amber N. Hurson
, Fiona M. Blows
, Manjeet K. Bolla
, Jodi L. Miller
, Roger L. Milne
, Hugo Horlings
, Alexandra J. van den Broek
, Clara Bodelon
, James M. Hodge
, Alpa V. Patel
, Lauren R. Teras
, Federico Canzian
, Rudolf Kaaks
, Hermann Brenner
, Ben Schöttker
, Sabine Behrens
, Jenny Chang-Claude
, Tabea Maurer

Nadia Obi, Fergus J. Couch, H. Raza Ali, Carlos Caldas, Irene Andrulis, Gord Glendon, Anna Marie Mulligan, Wilma Mesker, Agnes Jager, Annette Heemskerk-Gerritsen, Peter Devilee, Scott M. Lawrence, Jolanta Lissowska, Karun Mutreja, Thomas Ahearn, Stephen Chanock, Maire A. Duggan, Diana Eccles, J. Louise Jones, Will Tapper, Antoinette Hollestelle, Maartje Hooning, John Martens, Carolien H.M. van Deurzen, Angela Cox, Simon S. Cross, Mikael Hartman, Jingmei Li, Thomas C. Putti, Ute Hamann, Muhammad Rashid, Ania Jakubowska, Nicki Camp, Melissa H. Cessna, Amy Berrington de Gonzalez, Katarzyna Bialkowska, Jacek Gronwald, Jan Lubiński, Siddhartha Yadav, Pietro Lio, Douglas F. Easton, Mustapha Abubakar, Montse Garcia-Closas, Paul D.P. Pharoah^*, Marjanka K. Schmidt

^*Corresponding author for this work

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

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Abstract

Breast cancer immune response is important to patient outcome, but the prognostic interaction between tissue-infiltrating immune cell (TIIC) types is not well-characterized. We evaluated the associations between CD8⁺, FOXP3+, CD20⁺, and CD163⁺ TIICs and breast cancer-specific survival (BCSS). We developed an AI in Halo to score TIIC percentage by compartment (overall, stromal, or intra-tumoral) in 99,051 microarray images from 12,285 female breast cancers. The associations between log-transformed TIIC scores and BCSS were assessed using Cox regression. CD8⁺ and FOXP3+ TIICs were associated with better BCSS in ER-negative disease; CD8⁺ and CD20⁺ TIICs were associated with a better prognosis in ER-positive disease; and CD163⁺ TIICs were associated with a poorer prognosis in ER-positive disease in multi-marker models. These results may have implications for breast cancer immunotherapy.

Original language	English
Article number	114759
Journal	iScience
Volume	29
Issue number	2
DOIs	https://doi.org/10.1016/j.isci.2026.114759
Publication status	Published - 20 Feb 2026

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Publisher Copyright:
© 2026 The Author(s)

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Bernstein, A. J., Keeman, R., Hurson, A. N., Blows, F. M., Bolla, M. K., Miller, J. L., Milne, R. L., Horlings, H., van den Broek, A. J., Bodelon, C., Hodge, J. M., Patel, A. V., Teras, L. R., Canzian, F., Kaaks, R., Brenner, H., Schöttker, B., Behrens, S., Chang-Claude, J., ... Schmidt, M. K. (2026). Compartment-specific tumor-infiltrating immune cells and prognosis in breast cancer. iScience, 29(2), Article 114759. https://doi.org/10.1016/j.isci.2026.114759

@article{c66442d97a564ec6b27d7ca955a7105c,

title = "Compartment-specific tumor-infiltrating immune cells and prognosis in breast cancer",

abstract = "Breast cancer immune response is important to patient outcome, but the prognostic interaction between tissue-infiltrating immune cell (TIIC) types is not well-characterized. We evaluated the associations between CD8+, FOXP3+, CD20+, and CD163+ TIICs and breast cancer-specific survival (BCSS). We developed an AI in Halo to score TIIC percentage by compartment (overall, stromal, or intra-tumoral) in 99,051 microarray images from 12,285 female breast cancers. The associations between log-transformed TIIC scores and BCSS were assessed using Cox regression. CD8+ and FOXP3+ TIICs were associated with better BCSS in ER-negative disease; CD8+ and CD20+ TIICs were associated with a better prognosis in ER-positive disease; and CD163+ TIICs were associated with a poorer prognosis in ER-positive disease in multi-marker models. These results may have implications for breast cancer immunotherapy.",

author = "Bernstein, \{Aaron J.\} and Renske Keeman and Hurson, \{Amber N.\} and Blows, \{Fiona M.\} and Bolla, \{Manjeet K.\} and Miller, \{Jodi L.\} and Milne, \{Roger L.\} and Hugo Horlings and \{van den Broek\}, \{Alexandra J.\} and Clara Bodelon and Hodge, \{James M.\} and Patel, \{Alpa V.\} and Teras, \{Lauren R.\} and Federico Canzian and Rudolf Kaaks and Hermann Brenner and Ben Sch{\"o}ttker and Sabine Behrens and Jenny Chang-Claude and Tabea Maurer and Nadia Obi and Couch, \{Fergus J.\} and Ali, \{H. Raza\} and Carlos Caldas and Irene Andrulis and Gord Glendon and Mulligan, \{Anna Marie\} and Wilma Mesker and Agnes Jager and Annette Heemskerk-Gerritsen and Peter Devilee and Lawrence, \{Scott M.\} and Jolanta Lissowska and Karun Mutreja and Thomas Ahearn and Stephen Chanock and Duggan, \{Maire A.\} and Diana Eccles and Jones, \{J. Louise\} and Will Tapper and Antoinette Hollestelle and Maartje Hooning and John Martens and \{van Deurzen\}, \{Carolien H.M.\} and Angela Cox and Cross, \{Simon S.\} and Mikael Hartman and Jingmei Li and Putti, \{Thomas C.\} and Ute Hamann and Muhammad Rashid and Ania Jakubowska and Nicki Camp and Cessna, \{Melissa H.\} and \{Berrington de Gonzalez\}, Amy and Katarzyna Bialkowska and Jacek Gronwald and Jan Lubi{\'n}ski and Siddhartha Yadav and Pietro Lio and Easton, \{Douglas F.\} and Mustapha Abubakar and Montse Garcia-Closas and Pharoah, \{Paul D.P.\} and Schmidt, \{Marjanka K.\}",

note = "Publisher Copyright: {\textcopyright} 2026 The Author(s)",

year = "2026",

month = feb,

day = "20",

doi = "10.1016/j.isci.2026.114759",

language = "English",

volume = "29",

journal = "iScience",

issn = "2589-0042",

publisher = "Elsevier Inc.",

number = "2",

}

Bernstein, AJ, Keeman, R, Hurson, AN, Blows, FM, Bolla, MK, Miller, JL, Milne, RL, Horlings, H, van den Broek, AJ, Bodelon, C, Hodge, JM, Patel, AV, Teras, LR, Canzian, F, Kaaks, R, Brenner, H, Schöttker, B, Behrens, S, Chang-Claude, J, Maurer, T, Obi, N, Couch, FJ, Ali, HR, Caldas, C, Andrulis, I, Glendon, G, Mulligan, AM, Mesker, W, Jager, A , Heemskerk-Gerritsen, A, Devilee, P, Lawrence, SM, Lissowska, J, Mutreja, K, Ahearn, T, Chanock, S, Duggan, MA, Eccles, D, Jones, JL, Tapper, W, Hollestelle, A, Hooning, M , Martens, J , van Deurzen, CHM, Cox, A, Cross, SS, Hartman, M, Li, J, Putti, TC, Hamann, U, Rashid, M, Jakubowska, A, Camp, N, Cessna, MH, Berrington de Gonzalez, A, Bialkowska, K, Gronwald, J, Lubiński, J, Yadav, S, Lio, P, Easton, DF, Abubakar, M, Garcia-Closas, M, Pharoah, PDP & Schmidt, MK 2026, 'Compartment-specific tumor-infiltrating immune cells and prognosis in breast cancer', iScience, vol. 29, no. 2, 114759. https://doi.org/10.1016/j.isci.2026.114759

TY - JOUR

T1 - Compartment-specific tumor-infiltrating immune cells and prognosis in breast cancer

AU - Bernstein, Aaron J.

AU - Keeman, Renske

AU - Hurson, Amber N.

AU - Blows, Fiona M.

AU - Bolla, Manjeet K.

AU - Miller, Jodi L.

AU - Milne, Roger L.

AU - Horlings, Hugo

AU - van den Broek, Alexandra J.

AU - Bodelon, Clara

AU - Hodge, James M.

AU - Patel, Alpa V.

AU - Teras, Lauren R.

AU - Canzian, Federico

AU - Kaaks, Rudolf

AU - Brenner, Hermann

AU - Schöttker, Ben

AU - Behrens, Sabine

AU - Chang-Claude, Jenny

AU - Maurer, Tabea

AU - Obi, Nadia

AU - Couch, Fergus J.

AU - Ali, H. Raza

AU - Caldas, Carlos

AU - Andrulis, Irene

AU - Glendon, Gord

AU - Mulligan, Anna Marie

AU - Mesker, Wilma

AU - Jager, Agnes

AU - Heemskerk-Gerritsen, Annette

AU - Devilee, Peter

AU - Lawrence, Scott M.

AU - Lissowska, Jolanta

AU - Mutreja, Karun

AU - Ahearn, Thomas

AU - Chanock, Stephen

AU - Duggan, Maire A.

AU - Eccles, Diana

AU - Jones, J. Louise

AU - Tapper, Will

AU - Hollestelle, Antoinette

AU - Hooning, Maartje

AU - Martens, John

AU - van Deurzen, Carolien H.M.

AU - Cox, Angela

AU - Cross, Simon S.

AU - Hartman, Mikael

AU - Li, Jingmei

AU - Putti, Thomas C.

AU - Hamann, Ute

AU - Rashid, Muhammad

AU - Jakubowska, Ania

AU - Camp, Nicki

AU - Cessna, Melissa H.

AU - Berrington de Gonzalez, Amy

AU - Bialkowska, Katarzyna

AU - Gronwald, Jacek

AU - Lubiński, Jan

AU - Yadav, Siddhartha

AU - Lio, Pietro

AU - Easton, Douglas F.

AU - Abubakar, Mustapha

AU - Garcia-Closas, Montse

AU - Pharoah, Paul D.P.

AU - Schmidt, Marjanka K.

PY - 2026/2/20

Y1 - 2026/2/20

N2 - Breast cancer immune response is important to patient outcome, but the prognostic interaction between tissue-infiltrating immune cell (TIIC) types is not well-characterized. We evaluated the associations between CD8+, FOXP3+, CD20+, and CD163+ TIICs and breast cancer-specific survival (BCSS). We developed an AI in Halo to score TIIC percentage by compartment (overall, stromal, or intra-tumoral) in 99,051 microarray images from 12,285 female breast cancers. The associations between log-transformed TIIC scores and BCSS were assessed using Cox regression. CD8+ and FOXP3+ TIICs were associated with better BCSS in ER-negative disease; CD8+ and CD20+ TIICs were associated with a better prognosis in ER-positive disease; and CD163+ TIICs were associated with a poorer prognosis in ER-positive disease in multi-marker models. These results may have implications for breast cancer immunotherapy.

AB - Breast cancer immune response is important to patient outcome, but the prognostic interaction between tissue-infiltrating immune cell (TIIC) types is not well-characterized. We evaluated the associations between CD8+, FOXP3+, CD20+, and CD163+ TIICs and breast cancer-specific survival (BCSS). We developed an AI in Halo to score TIIC percentage by compartment (overall, stromal, or intra-tumoral) in 99,051 microarray images from 12,285 female breast cancers. The associations between log-transformed TIIC scores and BCSS were assessed using Cox regression. CD8+ and FOXP3+ TIICs were associated with better BCSS in ER-negative disease; CD8+ and CD20+ TIICs were associated with a better prognosis in ER-positive disease; and CD163+ TIICs were associated with a poorer prognosis in ER-positive disease in multi-marker models. These results may have implications for breast cancer immunotherapy.

UR - https://www.scopus.com/pages/publications/105029682997

U2 - 10.1016/j.isci.2026.114759

DO - 10.1016/j.isci.2026.114759

M3 - Article

AN - SCOPUS:105029682997

SN - 2589-0042

VL - 29

JO - iScience

JF - iScience

IS - 2

M1 - 114759

ER -

Compartment-specific tumor-infiltrating immune cells and prognosis in breast cancer

Abstract

Bibliographical note

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