Department of Oncological Sciences, Tisch Cancer Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Icahn 15-75B, New York, NY 10029, USA.
Immunol Res. 2012 Dec;54(1-3):262-5. doi: 10.1007/s12026-012-8319-1.
Identifying the appropriate drug targets for the development of a novel anti-tumor immunotherapy is one of the most risky steps in the drug development cycle. We have identified a hematopoietic cell-restricted serine/threonine kinase, hematopoietic progenitor kinase 1 (HPK1), as a possible target for therapeutic intervention. Targeted disruption of HPK1 alleles confers T cells with an elevated Th1 cytokine production in response to TCR engagement. HPK1 (-/-) T cells proliferate more rapidly than the haplotype-matched wild-type counterpart and are resistant to prostaglandin E2 (PGE(2))-mediated suppression. Most strikingly, mice that received adoptive transfer of HPK1 (-/-) T cells became resistant to lung tumor growth. Also, the loss of HPK1 from dendritic cells (DCs) endows them with superior antigen presentation ability, enabling HPK1 (-/-) DCs to elicit a more potent anti-tumor immune response when used as cancer vaccine. It is probable that blocking the HPK1 kinase activity with a small molecule inhibitor may activate the superior anti-tumor activity of both cell types, resulting in a synergistic amplification of anti-tumor potential. Given that HPK1 is not expressed in any major organs, it is less likely that an inhibitor of HPK1 kinase activity would cause any serious side effects.
确定新型抗肿瘤免疫疗法的合适药物靶点是药物开发周期中最具风险的步骤之一。我们已经确定了一种造血细胞特异性丝氨酸/苏氨酸激酶，造血祖细胞激酶 1（HPK1），作为治疗干预的可能靶点。靶向破坏 HPK1 等位基因可使 T 细胞在 TCR 结合时产生更高水平的 Th1 细胞因子。HPK1（-/-）T 细胞比具有相同单倍型的野生型对照细胞增殖更快，并且对前列腺素 E2（PGE（2））介导的抑制作用具有抗性。最引人注目的是，接受 HPK1（-/-）T 细胞过继转移的小鼠对肺肿瘤生长具有抗性。此外，从树突状细胞（DC）中丢失 HPK1 赋予它们更好的抗原呈递能力，使得 HPK1（-/-）DC 用作癌症疫苗时能够引发更有效的抗肿瘤免疫反应。用小分子抑制剂阻断 HPK1 激酶活性可能会激活这两种细胞类型的优异抗肿瘤活性，从而协同放大抗肿瘤潜能。鉴于 HPK1 不在任何主要器官中表达，因此 HPK1 激酶活性的抑制剂不太可能引起任何严重的副作用。
