TY - JOUR
T1 - HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors
AU - Guan, Lei
AU - Wu, Bin
AU - Li, Ting
AU - Beer, Lynn A.
AU - Sharma, Gaurav
AU - Li, Mingyue
AU - Lee, Chin Nien
AU - Liu, Shujing
AU - Yang, Changsong
AU - Huang, Lili
AU - Frederick, Dennie T.
AU - Boland, Genevieve M.
AU - Shao, Guangcan
AU - Svitkina, Tatyana M.
AU - Cai, Kathy Q.
AU - Chen, Fangping
AU - Dong, Meng Qiu
AU - Mills, Gordon B.
AU - Schuchter, Lynn M.
AU - Karakousis, Giorgos C.
AU - Mitchell, Tara C.
AU - Flaherty, Keith T.
AU - Speicher, David W.
AU - Chen, Youhai H.
AU - Herlyn, Meenhard
AU - Amaravadi, Ravi K.
AU - Xu, Xiaowei
AU - Guo, Wei
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - The lack of tumor infiltration by CD8+ T cells is associated with poor patient response to anti-PD-1 therapy. Understanding how tumor infiltration is regulated is key to improving treatment efficacy. Here, we report that phosphorylation of HRS, a pivotal component of the ESCRT complex involved in exosome biogenesis, restricts tumor infiltration of cytolytic CD8+ T cells. Following ERK-mediated phosphorylation, HRS interacts with and mediates the selective loading of PD-L1 to exosomes, which inhibits the migration of CD8+ T cells into tumors. In tissue samples from patients with melanoma, CD8+ T cells are excluded from the regions where tumor cells contain high levels of phosphorylated HRS. In murine tumor models, overexpression of phosphorylated HRS increases resistance to anti-PD-1 treatment, whereas inhibition of HRS phosphorylation enhances treatment efficacy. Our study reveals a mechanism by which phosphorylation of HRS in tumor cells regulates anti-tumor immunity by inducing PD-L1+ immunosuppressive exosomes, and suggests HRS phosphorylation blockade as a potential strategy to improve the efficacy of cancer immunotherapy.
AB - The lack of tumor infiltration by CD8+ T cells is associated with poor patient response to anti-PD-1 therapy. Understanding how tumor infiltration is regulated is key to improving treatment efficacy. Here, we report that phosphorylation of HRS, a pivotal component of the ESCRT complex involved in exosome biogenesis, restricts tumor infiltration of cytolytic CD8+ T cells. Following ERK-mediated phosphorylation, HRS interacts with and mediates the selective loading of PD-L1 to exosomes, which inhibits the migration of CD8+ T cells into tumors. In tissue samples from patients with melanoma, CD8+ T cells are excluded from the regions where tumor cells contain high levels of phosphorylated HRS. In murine tumor models, overexpression of phosphorylated HRS increases resistance to anti-PD-1 treatment, whereas inhibition of HRS phosphorylation enhances treatment efficacy. Our study reveals a mechanism by which phosphorylation of HRS in tumor cells regulates anti-tumor immunity by inducing PD-L1+ immunosuppressive exosomes, and suggests HRS phosphorylation blockade as a potential strategy to improve the efficacy of cancer immunotherapy.
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U2 - 10.1038/s41467-022-31713-6
DO - 10.1038/s41467-022-31713-6
M3 - Article
C2 - 35835783
AN - SCOPUS:85134092715
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4078
ER -