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Spatial predictors of immunotherapy response in triple-negative breast cancer.

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Danenberg, Esther 
Huang, Chiun-Sheng 
Callari, Maurizio 


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.


Acknowledgements: We thank the patients, investigators and study personnel who supported the NeoTRIPaPDL1 trial. We are also grateful for the technical support from the core facilities at the Cancer Research UK (CRUK) Cambridge Institute, in particular Flow Cytometry and Histology. This research was funded by CRUK (grant nos. A25815, A27463 and A29580). H.R.A. was supported by a CRUK Clinician Scientist Fellowship (grant no. A25815). The research leading to these results was also supported in part by the Associazione Italiana per la Ricerca sul Cancro (grant no. IG 2018 - ID. 21787 to G.B.) and the Breast Cancer Research Foundation (BCRF; grant no. 20–181 to L.G.). The NeoTRIPaPDL1 trial was supported by Fondazione Michelangelo and by unrestricted grants and free study drugs from Hoffman-La Roche, Ltd, Switzerland and Celgene, a Bristol Myers Squibb Company, Switzerland; in addition, it has been supported by the BCRF (grant no. 18–181 to L.G.). C.-S.H. and the Taiwan Breast Cancer Consortium received funding from the Ministry of Science and Technology, Executive Yuan, ROC, Taiwan (grant nos. MOST 109-2321-B-002-038-, MOST 108-2321-B-002-042-, MOST 107-2321-B-002-034- and MOST 106-2321-B-002-028-) and the Ministry of Health and Welfare of Taiwan (grant nos. MOHW 112-TDU-B-211-144002, MOHW111-TDU-B-211-134002 and MOHW110-TDU-B-211-124002). L.D.M. was funded by Associazione Italiana per la Ricerca sul Cancro (grant no. IG 2017 – ID. 20760).


Humans, B-Lymphocytes, Biopsy, CD8-Positive T-Lymphocytes, Granzymes, Histocompatibility Antigens Class II, Immunotherapy, Lewis X Antigen, Neoadjuvant Therapy, Precision Medicine, Prognosis, Randomized Controlled Trials as Topic, T-Lymphocytes, Triple Negative Breast Neoplasms

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