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Dynamic Changes in the NK-, Neutrophil-, and B-cell Immunophenotypes Relevant in High Metastatic Risk Post Neoadjuvant Chemotherapy–Resistant Early Breast Cancers

Research output: Contribution to journalArticlepeer-review

Patrycja Gazinska, Charlotte Milton, Jacopo Iacovacci, Joseph Ward, Richard Buus, Thanussuyah Alaguthurai, Rosalind Graham, Ayse Akarca, Esther Lips, Kalnisha Naidoo, Jelle Wesseling, Teresa Marafioti, Maggie Cheang, Cheryl Gillett, Yin Wu, Aadil Khan, Alan Melcher, Roberto Salgado, Mitch Dowsett, Andrew Tutt & 3 more Ioannis Roxanis, Syed Haider, Sheeba Irshad

Original languageEnglish
Pages (from-to)4494-4508
Number of pages15
JournalClinical Cancer Research
Volume28
Issue number20
DOIs
Accepted/In press12 Aug 2022
Published14 Oct 2022

Bibliographical note

Funding Information: This research was supported by grants from Cancer Research UK to S. Irshad (C56773/A24869) and program grants from Breast Cancer Now to A. Tutt at King’s College London and to the Breast Cancer Now Toby Robins Research Center at the Institute of Cancer Research, London. The work was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’sand St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Funding Information: R. Buus reports personal fees from NanoString Technologies outside the submitted work. T. Alaguthurai reports grants from CRUK during the conduct of the study. R. Graham reports grants from CRUK during the conduct of the study. J. Wesseling reports research funding for Cancer Grand Challenge from Cancer Research UK and KWF Dutch Cancer Society, focused on Ductal Carcinoma In Situ. M. Cheang reports personal fees from Advisory, grants from Eli Lilly, and grants from AstraZeneca outside the submitted work; in addition, M. Cheang has a patent for PAM50/ Bioclassifier with royalties paid from Veracyte. R. Salgado reports other support from BMS, Exact Sciences, and Merck outside the submitted work. M. Dowsett reports personal fees from AstraZeneca, Lilly, Roche, Radius, H3 Biomedicine, and G1 outside the submitted work. A.N. Tutt reports personal fees from Pfizer, Vertex, MD Anderson, Merck KGAA, Artios, Prime Oncology, Medscape Education, EMPartners, Inbiomotion, Gilead, GBCC, Cancer Panel, Research to practice, SABCS, and Penn Medicine, other support from CRUK, AZ Symposium at ESMO, GE Healthcare, VJ Oncology, Gilead, AstraZeneca, and Innovation in Breast Cancer Symposium, and AACR, personal fees and other support from AstraZeneca, grants and other support from AstraZeneca, and grants from Myriad genetic, MERCK KGAA, Medivation, CRUK, and Breast Cancer Now outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: © 2022 The Authors.

King's Authors

Abstract

Purpose:
To identify potential immune targets in post-neoadjuvant chemotherapy (NAC)–resistant triple-negative breast cancer (TNBC) and ER+HER2– breast cancer disease.

Experimental Design:
Following pathology review, 153 patients were identified as having residual cancer burden (RCB) II/III disease (TNBC n = 80; ER+HER2–n = 73). Baseline pre-NAC samples were available for evaluation for 32 of 80 TNBC and 36 of 73 ER+HER2– cases. Bright-field hematoxylin and eosin assessment allowed for tumor-infiltrating lymphocyte (TIL) evaluation in all cases. Multiplexed immunofluorescence was used to identify the abundance and distribution of immune cell subsets. Levels of checkpoints including PD-1/PD-L1 expression were also quantified. Findings were then validated using expression profiling of cancer and immune-related genes. Cytometry by time-of-flight characterized the dynamic changes in circulating immune cells with NAC.

Results:
RCB II/III TNBC and ER+HER2– breast cancer were immunologically “cold” at baseline and end of NAC. Although the distribution of immune cell subsets across subtypes was similar, the mRNA expression profiles were both subtype- and chemotherapy-specific. TNBC RCB II/III disease was enriched with genes related to neutrophil degranulation, and displayed strong interplay across immune and cancer pathways. We observed similarities in the dynamic changes in B-cell biology following NAC irrespective of subtype. However, NAC induced changes in the local and circulating tumor immune microenvironment (TIME) that varied by subtype and response. Specifically, in TNBC residual disease, we observed downregulation of stimulatory (CD40/OX40L) and inhibitory (PD-L1/PD-1) receptor expression and an increase in NK cell populations (especially non-cytolytic, exhausted CD56dimCD16–) within both the local TIME and peripheral white cell populations.

Conclusions:
This study identifies several potential immunologic pathways in residual disease, which may be targeted to benefit high-risk patients.

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