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Translational Cancer Mechanisms and Therapy

Changes in Peripheral and Local Tumor Immunity after Neoadjuvant Chemotherapy Reshape Clinical Outcomes in Patients with Breast Cancer

Margaret L. Axelrod, Mellissa J. Nixon, Paula I. Gonzalez-Ericsson, Riley E. Bergman, Mark A. Pilkinton, Wyatt J. McDonnell, Violeta Sanchez, Susan R. Opalenik, Sherene Loi, Jing Zhou, Sean Mackay, Brent N. Rexer, Vandana G. Abramson, Valerie M. Jansen, Simon Mallal, Joshua Donaldson, Sara M. Tolaney, Ian E. Krop, Ana C. Garrido-Castro, Jonathan D. Marotti, Kevin Shee, Todd W. Miller, Melinda E. Sanders, Ingrid A. Mayer, Roberto Salgado and Justin M. Balko
Margaret L. Axelrod
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
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  • ORCID record for Margaret L. Axelrod
Mellissa J. Nixon
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
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  • ORCID record for Mellissa J. Nixon
Paula I. Gonzalez-Ericsson
2Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, Tennessee.
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  • ORCID record for Paula I. Gonzalez-Ericsson
Riley E. Bergman
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
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Mark A. Pilkinton
3Department of Infectious Disease, Vanderbilt University Medical Center, Nashville, Tennessee.
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Wyatt J. McDonnell
3Department of Infectious Disease, Vanderbilt University Medical Center, Nashville, Tennessee.
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  • ORCID record for Wyatt J. McDonnell
Violeta Sanchez
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
2Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, Tennessee.
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Susan R. Opalenik
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
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Sherene Loi
4Department of Oncology, University of Melbourne and Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
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  • ORCID record for Sherene Loi
Jing Zhou
5IsoPlexis Corporation, Branford, Connecticut.
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Sean Mackay
5IsoPlexis Corporation, Branford, Connecticut.
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Brent N. Rexer
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
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Vandana G. Abramson
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
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Valerie M. Jansen
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
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Simon Mallal
3Department of Infectious Disease, Vanderbilt University Medical Center, Nashville, Tennessee.
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Joshua Donaldson
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
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Sara M. Tolaney
6Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
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Ian E. Krop
6Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
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Ana C. Garrido-Castro
6Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
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Jonathan D. Marotti
7Department of Pathology & Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
8Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
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Kevin Shee
9Department of Molecular & Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
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Todd W. Miller
8Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
9Department of Molecular & Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
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Melinda E. Sanders
2Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, Tennessee.
10Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
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Ingrid A. Mayer
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
2Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, Tennessee.
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Roberto Salgado
4Department of Oncology, University of Melbourne and Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
11Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium.
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Justin M. Balko
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
2Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, Tennessee.
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  • For correspondence: justin.balko@vumc.org
DOI: 10.1158/1078-0432.CCR-19-3685 Published November 2020
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Abstract

Purpose: The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME).

Experimental Design: We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1–high (PD-1HI) CD8+ peripheral T cells and examination of a cytolytic gene signature in whole blood.

Results: In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden.

Conclusions: We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence.

This article is featured in Highlights of This Issue, p. 5541

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2020;26:5668–81

  • Received November 12, 2019.
  • Revision received May 21, 2020.
  • Accepted August 18, 2020.
  • Published first August 21, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 26 (21)
November 2020
Volume 26, Issue 21
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Changes in Peripheral and Local Tumor Immunity after Neoadjuvant Chemotherapy Reshape Clinical Outcomes in Patients with Breast Cancer
Margaret L. Axelrod, Mellissa J. Nixon, Paula I. Gonzalez-Ericsson, Riley E. Bergman, Mark A. Pilkinton, Wyatt J. McDonnell, Violeta Sanchez, Susan R. Opalenik, Sherene Loi, Jing Zhou, Sean Mackay, Brent N. Rexer, Vandana G. Abramson, Valerie M. Jansen, Simon Mallal, Joshua Donaldson, Sara M. Tolaney, Ian E. Krop, Ana C. Garrido-Castro, Jonathan D. Marotti, Kevin Shee, Todd W. Miller, Melinda E. Sanders, Ingrid A. Mayer, Roberto Salgado and Justin M. Balko
Clin Cancer Res November 1 2020 (26) (21) 5668-5681; DOI: 10.1158/1078-0432.CCR-19-3685

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Changes in Peripheral and Local Tumor Immunity after Neoadjuvant Chemotherapy Reshape Clinical Outcomes in Patients with Breast Cancer
Margaret L. Axelrod, Mellissa J. Nixon, Paula I. Gonzalez-Ericsson, Riley E. Bergman, Mark A. Pilkinton, Wyatt J. McDonnell, Violeta Sanchez, Susan R. Opalenik, Sherene Loi, Jing Zhou, Sean Mackay, Brent N. Rexer, Vandana G. Abramson, Valerie M. Jansen, Simon Mallal, Joshua Donaldson, Sara M. Tolaney, Ian E. Krop, Ana C. Garrido-Castro, Jonathan D. Marotti, Kevin Shee, Todd W. Miller, Melinda E. Sanders, Ingrid A. Mayer, Roberto Salgado and Justin M. Balko
Clin Cancer Res November 1 2020 (26) (21) 5668-5681; DOI: 10.1158/1078-0432.CCR-19-3685
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