Abstract：
:We examined hematopoietic protein kinase 1 (HPK1), whose reliance on scaffold versus kinase functions for negative immune cell regulation is poorly understood and critical to its assessment as a viable drug target. We identify kinase-dependent roles for HPK1 in CD8 T cells that restrict their anti-viral and anti-tumor responses by using HPK1 kinase-dead (HPK1.kd) knockin mice. Loss of HPK1 kinase function enhanced T cell receptor signaling and cytokine secretion in a T-cell-intrinsic manner. In response to chronic lymphocytic choriomeningitis virus (LCMV) infection or tumor challenge, viral clearance and tumor growth inhibition were enhanced in HPK1.kd mice, accompanied by an increase in effector CD8 T cell function. Co-blockade of PD-L1 further enhanced T effector cell function, resulting in superior anti-viral and anti-tumor immunity over single target blockade. These results identify the importance of HPK1 kinase activity in the negative regulation of CD8 effector functions, implicating its potential as a cancer immunotherapy target.
journal_name
Cell Repjournal_title
Cell reportsauthors
Hernandez S,Qing J,Thibodeau RH,Du X,Park S,Lee HM,Xu M,Oh S,Navarro A,Roose-Girma M,Newman RJ,Warming S,Nannini M,Sampath D,Kim JM,Grogan JL,Mellman Idoi
10.1016/j.celrep.2018.09.012subject
Has Abstractpub_date
2018-10-02 00:00:00pages
80-94issue
1issn
2211-1247pii
S2211-1247(18)31442-6journal_volume
25pub_type
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