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<p>Immune checkpoint inhibition (ICI) benefits only a subset of patients with metastatic triple-negative breast cancer and determinants of response remain unclear. We assembled a longitudinal cohort of 103 female patients from the phase 2 TONIC trial, with samples spanning primary tumors, pretreatment metastases and on-treatment metastases during nivolumab therapy. We profiled 37 proteins in 270 tumors using highly multiplexed imaging and developed SpaceCat, an open-source pipeline that extracts more than 800 imaging features per sample, including cell density, diversity, spatial interactions and functional marker expression. Metastatic but not primary tumors contained features predictive of outcome. Spatial metrics such as immune diversity and T cell infiltration at tumor borders were most informative, while ratios of T cells to cancer cells and PDL1 on myeloid cells were also associated with response. Multivariate models stratified patients with the highest performance on treatment (area under the curve = 0.90). Bulk RNA-seq confirmed the predictive value of on-treatment samples. These findings highlight the value of longitudinal profiling to resolve evolving tumor microenvironment dynamics driving ICI response.</p>

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Temporal and spatial composition of the tumor microenvironment predicts response to immune checkpoint inhibition in metastatic TNBC

  • 期刊论文

  • 发表日期：

    2026年2月18日

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  • Noah F. Greenwald,
  • Iris Nederlof,
  • Cameron Sowers,
  • Daisy Yi Ding,
  • Seongyeol Park,
  • Alex Kong,
  • Kathleen E. Houlahan,
  • Sricharan Reddy Varra,
  • Manon de Graaf,
  • Veerle Geurts,
  • Candace C. Liu,
  • Jolene S. Ranek,
  • Leonie Voorwerk,
  • Michiel de Maaker,
  • Adam Kagel,
  • Erin McCaffrey,
  • Aziz Khan,
  • Christine Yiwen Yeh,
  • Christine Camacho Fullaway,
  • Zumana Khair,
  • Brennan G. Simon,
  • Yunhao Bai,
  • Hadeesha Piyadasa,
  • Tyler Risom,
  • Alea Delmastro,
  • Felix J. Hartmann,
  • Lise Mangiante,
  • Cristina Sotomayor-Vivas,
  • Sean C. Bendall,
  • Ton N. Schumacher,
  • Zhicheng Ma,
  • Marc Bosse,
  • Marc J. van de Vijver,
  • Robert Tibshirani,
  • Hugo M. Horlings,
  • Christina Curtis,
  • Marleen Kok,
  • Michael Angelo

摘要

Immune checkpoint inhibition (ICI) benefits only a subset of patients with metastatic triple-negative breast cancer and determinants of response remain unclear. We assembled a longitudinal cohort of 103 female patients from the phase 2 TONIC trial, with samples spanning primary tumors, pretreatment metastases and on-treatment metastases during nivolumab therapy. We profiled 37 proteins in 270 tumors using highly multiplexed imaging and developed SpaceCat, an open-source pipeline that extracts more than 800 imaging features per sample, including cell density, diversity, spatial interactions and functional marker expression. Metastatic but not primary tumors contained features predictive of outcome. Spatial metrics such as immune diversity and T cell infiltration at tumor borders were most informative, while ratios of T cells to cancer cells and PDL1 on myeloid cells were also associated with response. Multivariate models stratified patients with the highest performance on treatment (area under the curve = 0.90). Bulk RNA-seq confirmed the predictive value of on-treatment samples. These findings highlight the value of longitudinal profiling to resolve evolving tumor microenvironment dynamics driving ICI response.