A PSAT1 buff of YBX1 transcriptionally sustains HLA-E-mediated evasion of NK immunity
Abstract
Despite great success in certain cancers, immunotherapy made little progress in treating immune cold tumors, largely attributed to an immune-suppressive tumor microenvironment with elusive mechanisms. Here, we report in prostate cancer cells a positive feedback loop driven by phosphoserine aminotransferase 1 (PSAT1) that could be targeted to render effective cytotherapy by natural killer (NK) cells. In the loop, PSAT1 increases Y-box binding protein 1 (YBX1) phosphorylation by microtubule affinity-regulating kinase 2, promoting its nuclear translocation to upregulate PSAT1 transcription. Meanwhile, YBX1 also promotes human leukocyte antigens E (HLA-E) transcription to inactivate NK cells. Consequently, the PSAT1 loop serves as a buff sustaining YBX1/HLA-E expression, suppressing NK killing of prostate cancer cells. Targeting loop molecules, such as PAST1, effectively potentiates tumor suppression by NK cells both in-vitro and in-vivo. Thus, our study uncovered a heretofore unrecognized nonautonomous mechanism for PSAT1, as well as a molecular buff for YBX1, to drive tumor growth by evading NK immunity, providing a promising target for NK cytotherapy of immune cold tumors.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Yangyi Zhang
Department of Oncology, Beijing Shijitan Hospital, Capital Medical University
He Ren
Department of Oncology, Beijing Shijitan Hospital, Capital Medical University
Chaobing Ma
Department of Oncology, Beijing Shijitan Hospital, Capital Medical University
Changhong Shi
Laboratory Animal Center, Air Force Medical University
Ruigang Yang
Academy of Military Medical Science, Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science
Chenxi Wang
Academy of Military Medical Science, Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science
Pengfei Feng
Academy of Military Medical Science, Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science
Bo Zhang
Chenyu Liu
Department of Oncology, Beijing Shijitan Hospital, Capital Medical University
Zubiao Niu
Academy of Military Medical Science, Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science
Yalan Yang
Department of Oncology, Beijing Shijitan Hospital, Capital Medical University
You Zheng
Academy of Military Medical Science, Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science
Zhuoran Sun
Department of Chemistry
Ying Zhang
Shinan Zhang
Department of Oncology, Beijing Shijitan Hospital, Capital Medical University
Gerry Melino
Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”
Hongyan Huang
Department of Oncology, Beijing Shijitan Hospital, Capital Medical University
Qiang Sun