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  3. Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies

Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies

  • Cancer Cell. 2020 Oct 12;38(4):551-566.e11. doi: 10.1016/j.ccell.2020.08.001.
Jingwen Si 1,  Xiangjun Shi 2,  Shuhao Sun 2,  Bin Zou 3,  Yaopeng Li 2,  Dongjie An 2,  Xingyu Lin 4,  Yan Gao 5,  Fei Long 6,  Bo Pang 7,  Xing Liu 8,  Tian Liu 9,  Wenna Chi 2,  Ligong Chen 2,  Dimiter S Dimitrov 10,  Yan Sun 11,  Xinru Du 12,  Wen Yin 13,  Guangxun Gao 14,  Junxia Min 15,  Lai Wei 16,  Xuebin Liao 17
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China; Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
  • 2 School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China.
  • 3 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 510060 Guangzhou, China.
  • 4 Zhuhai Yufan Biotechnologies Co., Ltd, Zhuhai, 519000 Guangdong, China.
  • 5 School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China; Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, 100026 Beijing, China.
  • 6 Xi'an Yufan Biotechnologies Co., Ltd, Xi'an, 710032 Shaanxi, China.
  • 7 Department of Clinical Laboratory, Guang'an Men Hospital, China Academy of Chinese Medical Sciences, 100053 Beijing, China.
  • 8 Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, 410013 Hunan, China.
  • 9 Department of Plastic Surgery, General Hospital of Southern Theater Command, PLA, Guangdong, 510010 Guangzhou, China.
  • 10 Center for Antibody Therapeutics, University of Pittsburgh, Pittsburgh, PA 15216, USA.
  • 11 Lanzhou Institute of Husbandry and Pharmaceutical Science of CAAS, Lanzhou, 730050 Gansu, China.
  • 12 Department of Orthopaedics, Beijing Chao-Yang Hospital, Capita Medical University, 100020 Beijing, China.
  • 13 Department of Transfusion Medicine, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032 Shaanxi, China.
  • 14 Department of Hematology, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032 Shaanxi, China.
  • 15 The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University, Hangzhou, 310058 Zhejiang, China.
  • 16 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 510060 Guangzhou, China. Electronic address: weil9@mail.sysu.edu.cn.
  • 17 School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, 100084 Beijing, China. Electronic address: liaoxuebin@mail.tsinghua.edu.cn.
PMID: 32860752 DOI: 10.1016/j.ccell.2020.08.001
Abstract

Ameliorating T cell exhaustion and enhancing effector function are promising strategies for the improvement of immunotherapies. Here, we show that the HPK1-NFκB-Blimp1 axis mediates T cell dysfunction. High expression of MAP4K1 (which encodes HPK1) correlates with increased T cell exhaustion and with worse patient survival in several Cancer types. In MAP4K1KO mice, tumors grow slower than in wild-type mice and infiltrating T cells are less exhausted and more active and proliferative. We further show that genetic depletion, pharmacological inhibition, or proteolysis targeting chimera (PROTAC)-mediated degradation of HPK1 improves the efficacy of CAR-T cell-based immunotherapies in diverse preclinical mouse models of hematological and solid tumors. These strategies are more effective than genetically depleting PD-1 in CAR-T cells. Thus, we demonstrate that HPK1 is a mediator of T cell dysfunction and an attractive druggable target to improve immune therapy responses.

Keywords

CAR-T; HPK1; PROTACs; T cell exhaustion; cancer immunotherapy.

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