CD8+ T cells inhibit metastasis and CXCL4 regulates its function

• Published in: British journal of cancer Vol. 125; no. 2; pp. 176 - 189
• Main Authors: Joseph, Robiya, Soundararajan, Rama, Vasaikar, Suhas, Yang, Fei, Allton, Kendra L., Tian, Lin, den Hollander, Petra, Isgandarova, Sevinj, Haemmerle, Monika, Mino, Barbara, Zhou, Tieling, Shin, Crystal, Martinez-Paniagua, Melisa, Sahin, Aysegul A., Rodriguez-Canales, Jaime, Gelovani, Juri, Chang, Jeffrey T., Acharya, Ghanashyam, Sood, Anil K., Wistuba, Ignacio I., Gibbons, Don L., Solis, Luisa M., Barton, Michelle C., Varadarajan, Navin, Rosen, Jeffrey M., Zhang, Xiang H., Mani, Sendurai A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.07.2021; Nature Publishing Group
• Subjects: 631/67/322; 631/67/580; Animal models; Animals; Bioluminescence; Biomedical and Life Sciences; Biomedicine; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Cancer Research; CD4 antigen; CD4 Antigens - genetics; CD8 antigen; CD8 Antigens - genetics; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - transplantation; Cell Line, Tumor; Drug Resistance; Epidemiology; Female; Gene Knockout Techniques; Humans; Immunohistochemistry; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Lymphocytes; Lymphocytes T; Metastases; Metastasis; Mice; Mice, Inbred NOD; Mice, Nude; Molecular Medicine; Monocytes; Myeloid-Derived Suppressor Cells - immunology; Neoplastic Cells, Circulating - immunology; Oncology; Platelet Factor 4 - administration & dosage; Platelet Factor 4 - metabolism; Platelet Factor 4 - pharmacology; Platelets; Suppressor cells; Survival Analysis; Transplantation, Isogeneic; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-021-01338-5

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.