TY - JOUR
T1 - CD8+ T cells inhibit metastasis and CXCL4 regulates its function
AU - Joseph, Robiya
AU - Soundararajan, Rama
AU - Vasaikar, Suhas
AU - Yang, Fei
AU - Allton, Kendra L.
AU - Tian, Lin
AU - den Hollander, Petra
AU - Isgandarova, Sevinj
AU - Haemmerle, Monika
AU - Mino, Barbara
AU - Zhou, Tieling
AU - Shin, Crystal
AU - Martinez-Paniagua, Melisa
AU - Sahin, Aysegul A.
AU - Rodriguez-Canales, Jaime
AU - Gelovani, Juri
AU - Chang, Jeffrey T.
AU - Acharya, Ghanashyam
AU - Sood, Anil K.
AU - Wistuba, Ignacio I.
AU - Gibbons, Don L.
AU - Solis, Luisa M.
AU - Barton, Michelle C.
AU - Varadarajan, Navin
AU - Rosen, Jeffrey M.
AU - Zhang, Xiang H.
AU - Mani, Sendurai A.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/7/20
Y1 - 2021/7/20
N2 - 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. [Figure not available: see fulltext.]
AB - 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. [Figure not available: see fulltext.]
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U2 - 10.1038/s41416-021-01338-5
DO - 10.1038/s41416-021-01338-5
M3 - Article
C2 - 33795809
AN - SCOPUS:85103565931
SN - 0007-0920
VL - 125
SP - 176
EP - 189
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 2
ER -