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

乳腺癌 基因签名 医学 免疫疗法 免疫学 三阴性乳腺癌 CD8型 化疗 生物标志物 细胞毒性T细胞 癌症 免疫系统 肿瘤科 癌症研究 内科学 基因表达 生物 基因 体外 生物化学
作者
Margaret L. Axelrod,Mellissa J. Nixon,Paula I. González-Ericsson,Riley E. Bergman,Mark A. Pilkinton,Wyatt J. McDonnell,Violeta Sánchez,Susan R. Opalenik,Sherene Loi,Jing Zhou,Sean Mackay,Brent N. Rexer,Vandana G. Abramson,Valerie M. Jansen,S. 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,Justin M. Balko
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:26 (21): 5668-5681 被引量:44
标识
DOI:10.1158/1078-0432.ccr-19-3685
摘要

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.
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