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.

41416_2021_1338_Figa_HTML.jpg (134 kB)
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