TY - JOUR
T1 - Claudin-12 Deficiency Inhibits Tumor Growth by Impairing Transendothelial Migration of Myeloid-Derived Suppressor Cells
AU - Cao, Hong
AU - Ni, Chen
AU - Han, Le
AU - Wang, Ruoqi
AU - Blasig, Rosel
AU - Haseloff, Reiner
AU - Qin, Yue
AU - Lan, Jie
AU - Lou, Xiaohan
AU - Ma, Pan
AU - Yao, Xiaohan
AU - Wang, Linlin
AU - Wang, Fei
AU - Zhu, Linyu
AU - Lei, Ningjing
AU - Blasig, Ingolf E.
AU - Qin, Zhihai
N1 - Publisher Copyright:
© 2022 American Association for Cancer Research
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Migration of myeloid-derived suppressor cells (MDSC) out of the circulation, across vascular walls, and into tumor is crucial for their immunosuppressive activity. A deeper understanding of critical junctional molecules and the regulatory mechanisms that mediate the extravasation of MDSCs could identify approaches to overcome cancer immunosuppression. In this study, we used mice deficient in tight junction protein Claudin-12 (Cldn12) compared with wild-type mice and found that loss of host Cldn12 inhibited the growth of transplanted tumors, reduced intratumoral accumulation of MDSCs, increased antitumor immune responses, and decreased tumor vascular density. Further studies revealed that Cldn12 expression on the cell surface of both MDSCs and endothelial cells (EC) is required for MDSCs transit across tumor vascular ECs. Importantly, expression of Cldn12 in MDSCs was modulated by GM-CSF in an AKT-dependent manner. Therefore, our results indicate that Cldn12 could serve as a promising target for restoring the antitumor response by interfering with MDSCs transendothelial migration. Significance: Claudin-12–mediated homotypic interactions are critical for migration of myeloid-derived suppressor cells across vascular walls into tumor tissue, providing a potential therapeutic approach to overcome cancer immunosuppression.
AB - Migration of myeloid-derived suppressor cells (MDSC) out of the circulation, across vascular walls, and into tumor is crucial for their immunosuppressive activity. A deeper understanding of critical junctional molecules and the regulatory mechanisms that mediate the extravasation of MDSCs could identify approaches to overcome cancer immunosuppression. In this study, we used mice deficient in tight junction protein Claudin-12 (Cldn12) compared with wild-type mice and found that loss of host Cldn12 inhibited the growth of transplanted tumors, reduced intratumoral accumulation of MDSCs, increased antitumor immune responses, and decreased tumor vascular density. Further studies revealed that Cldn12 expression on the cell surface of both MDSCs and endothelial cells (EC) is required for MDSCs transit across tumor vascular ECs. Importantly, expression of Cldn12 in MDSCs was modulated by GM-CSF in an AKT-dependent manner. Therefore, our results indicate that Cldn12 could serve as a promising target for restoring the antitumor response by interfering with MDSCs transendothelial migration. Significance: Claudin-12–mediated homotypic interactions are critical for migration of myeloid-derived suppressor cells across vascular walls into tumor tissue, providing a potential therapeutic approach to overcome cancer immunosuppression.
UR - http://www.scopus.com/inward/record.url?scp=85134083585&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-21-3896
DO - 10.1158/0008-5472.CAN-21-3896
M3 - Article
C2 - 35580275
AN - SCOPUS:85134083585
SN - 0008-5472
VL - 82
SP - 2472
EP - 2484
JO - Cancer research
JF - Cancer research
IS - 13
ER -