Publication Date
7-1-2021
Journal
British Journal of Cancer
DOI
10.1038/s41416-021-01338-5
PMID
33795809
PMCID
PMC8292398
PubMedCentral® Posted Date
4-1-2021
PubMedCentral® Full Text Version
Post-Print
Published Open-Access
yes
Keywords
Animals, Breast Neoplasms, CD4 Antigens, CD8 Antigens, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Female, Gene Knockout Techniques, Humans, Lung Neoplasms, Mice, Mice, Inbred NOD, Mice, Nude, Myeloid-Derived Suppressor Cells, Neoplastic Cells, Circulating, Platelet Factor 4, Survival Analysis, Transplantation, Isogeneic, Xenograft Model Antitumor Assays, Tumour immunology, Metastasis
Abstract
Background
The mechanism by which immune cells regulate metastasis is unclear. Understanding the role of immune cells in metastasis will guide the development of treatments improving patient survival.
Methods
We used syngeneic orthotopic mouse tumour models (wild-type, NOD/scid and Nude), employed knockout (CD8 and CD4) models and administered CXCL4. Tumours and lungs were analysed for cancer cells by bioluminescence, and circulating tumour cells were isolated from blood. Immunohistochemistry on the mouse tumours was performed to confirm cell type, and on a tissue microarray with 180 TNBCs for human relevance. TCGA data from over 10,000 patients were analysed as well.
Results
We reveal that intratumoral immune infiltration differs between metastatic and non-metastatic tumours. The non-metastatic tumours harbour high levels of CD8+ T cells and low levels of platelets, which is reverse in metastatic tumours. During tumour progression, platelets and CXCL4 induce differentiation of monocytes into myeloid-derived suppressor cells (MDSCs), which inhibit CD8+ T-cell function. TCGA pan-cancer data confirmed that CD8lowPlatelethigh patients have a significantly lower survival probability compared to CD8highPlateletlow.
Conclusions
CD8+ T cells inhibit metastasis. When the balance between CD8+ T cells and platelets is disrupted, platelets produce CXCL4, which induces MDSCs thereby inhibiting the CD8+ T-cell function.
Graphical Abstract
Comments
Associated Data