Spatial predictors of immunotherapy response in triple-negative breast cancer

Xiao Qian Wang, Esther Danenberg, Chiun-Sheng Huang, Daniel Egle, Maurizio Callari, Begoña Bermejo, Matteo Dugo, Claudio Zamagni, Marc Thill, Anton Anton, Stefania Zambelli, Stefania Russo, Eva Maria Ciruelos, Richard Greil, Balázs Győrffy, Vladimir Semiglazov, Marco Colleoni, Catherine M. Kelly, Gabriella Mariani, Lucia Mastro, Olivia Biasi, Robert S. Seitz, Pinuccia Valagussa, Giuseppe Viale, Luca Gianni, Giampaolo Bianchini () and H. Raza Ali ()
Additional contact information
Xiao Qian Wang: University of Cambridge
Esther Danenberg: University of Cambridge
Chiun-Sheng Huang: National Taiwan University Hospital, College of Medicine, National Taiwan University and Taiwan Breast Cancer Consortium
Daniel Egle: Medical University Innsbruck
Maurizio Callari: Fondazione Michelangelo
Begoña Bermejo: Hospital Clínico Universitario de Valencia, Biomedical Research Institute INCLIVA
Matteo Dugo: San Raffaele Hospital
Claudio Zamagni: IRCCS Azienda Ospedaliero-universitaria di Bologna
Marc Thill: Agaplesion Markus Krankenhaus
Anton Anton: Hospital Universitario Miguel Servet
Stefania Zambelli: San Raffaele Hospital
Stefania Russo: Azienda Sanitaria Universitaria Friuli Centrale
Eva Maria Ciruelos: Hospital Universitario 12 de Octubre
Richard Greil: Paracelsus Medical University Salzburg
Balázs Győrffy: Semmelweis University
Vladimir Semiglazov: NN Petrov Research Institute of Oncology
Marco Colleoni: IRCCS
Catherine M. Kelly: Dublin and Cancer Trials Ireland Breast Group
Gabriella Mariani: Fondazione IRCSS - Istituto Nazionale Tumori
Lucia Mastro: UO Clinica di Oncologia Medica
Olivia Biasi: IRCCS
Robert S. Seitz: Oncocyte Corporation
Pinuccia Valagussa: Fondazione Michelangelo
Giuseppe Viale: IRCCS
Luca Gianni: Fondazione Michelangelo
Giampaolo Bianchini: Fondazione Michelangelo
H. Raza Ali: University of Cambridge

Nature, 2023, vol. 621, issue 7980, 868-876

Abstract: Abstract Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear1. Because ICB targets cell–cell interactions2, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry3 to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8+TCF1+T cells and MHCII+ cancer cells were dominant predictors of response, followed by cancer–immune interactions with B cells and granzyme B+ T cells. On-treatment, responsive tumours contained abundant granzyme B+ T cells, whereas resistant tumours were characterized by CD15+ cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.

Date: 2023
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DOI: 10.1038/s41586-023-06498-3

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