CD8+ T cells inhibit metastasis and CXCL4 regulates its function

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 CD8(low)Platelet(high) patients have a significantly lower survival probability compared to CD8(high)Platelet(low). 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.

Automated summary

We found that immune infiltration within tumors differs between metastatic and non-metastatic tumors. Non-metastatic tumors have high levels of CD8(+) T cells and low levels of platelets, whereas this is reversed in metastatic tumors. Platelets and CXCL4 induce differentiation of monocytes into myeloid-derived suppressor cells (MDSCs) during tumor progression, inhibiting the function of CD8(+) T cells. TCGA data confirmed that patients with low CD8 levels and high platelet levels have lower survival probabilities compared to patients with high CD8 levels and low platelet levels.