The Kinase Activity of Hematopoietic Progenitor Kinase 1 Is Essential for the Regulation of T Cell Function.

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 Rep

journal_title

Cell reports

authors

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 I

doi

10.1016/j.celrep.2018.09.012

subject

Has Abstract

pub_date

2018-10-02 00:00:00

pages

80-94

issue

1

issn

2211-1247

pii

S2211-1247(18)31442-6

journal_volume

25

pub_type

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