期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 9, 页码 3678-3687出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1817652116
关键词
TNBC; TIL; tumor-cell clusters; ECM; chemokine
资金
- National Science Foundation (NSF) Center for Theoretical Biological Physics [NSF PHY-1427654]
- NSF [DMS-1361411]
- V Foundation
- Consortium Quebecois sur la Decouverte du Medicament/Quebec Consortium for Drug [52811]
- National Institutes of Health [2P01CA097189-06]
- Merck, Sharpe & Dohme Corp./McGill Faculty of Medicine [238371]
- Database and Tissue Bank Axis of the Reseau de Recherche en Cancer of the Fonds de Recherche du Quebec-Sante
- Quebec Breast Cancer Foundation
- Charlotte and Leo Karassik Oncology fellowship
Infiltration of CD8(+) T lymphocytes into solid tumors is associated with good prognosis in various types of cancer, including triple-negative breast cancer (TNBC). However, the mechanisms underlying different infiltration levels are largely unknown. Here, we have characterized the spatial profile of CD8(+) T cells around tumor cell clusters (tightly connected tumor cells) in the core and margin regions in TNBC patient samples. We found that in some patients, the CD8(+) T cell density first decreases when moving in from the boundary of the tumor cell clusters and then rises again when approaching the center. To explain various infiltration profiles, we modeled the dynamics of T cell density via partial differential equations. We spatially modulated the diffusion/chemotactic coefficients of T cells (to mimic physical barriers) or introduced the localized secretion of a diffusing T cell chemorepellent. Combining the spatial-profile analysis and the modeling led to support for the second idea; i. e., there exists a possible chemorepellent inside tumor cell clusters, which prevents CD8(+) T cells from infiltrating into tumor cell clusters. This conclusion was consistent with an investigation into the properties of collagen fibers which suggested that variations in desmoplastic elements does not limit infiltration of CD8(+) T lymphocytes, as we did not observe significant correlations between the level of T cell infiltration and fiber properties. Our work provides evidence that CD8(+) T cells can cross typical fibrotic barriers and thus their infiltration into tumor clusters is governed by other mechanisms possibly involving a local repellent.
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