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Hematopoietic Progenitor Kinase 1 Is a Negative Regulator of Dendritic Cell Activation

Saba Alzabin^1,*, Nina Bhardwaj^*, Friedemann Kiefer, Sansana Sawasdikosol^2,3,* and Steven Burakoff^2,*

^* New York University Cancer Institute, Department of Pathology, New York University School of Medicine, New York, NY 10016; and Department of Vascular Cell Biology, Max-Planck-Institute for Molecular Biomedicine, Muenster, Germany

Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted member of the Ste20 kinases that acts as a negative regulator of T cell functions through the AP-1, NFAT, and NFB pathways. Using HPK1-deficient (HPK1^–/–) mice, we report in this study a novel role for HPK1 in dendritic cells (DCs). Specifically, we observed that matured HPK1^–/– bone marrow-derived DCs (BMDCs) are superior to their wild-type (WT) counterpart in stimulating T cell proliferation in vivo and in vitro. Several characteristics of HPK1^–/– BMDCs may account for this enhanced activity: Matured HPK1^–/– BMDCs express higher levels of costimulatory molecules CD80, CD86, and I-A^b as well as produce more proinflammatory cytokines IL-12, IL-1β, TNF-, and IL-6 than their WT littermates. The role of HPK1 as a proapoptotic molecule was assessed post activation with LPS, and results indicated that HPK1^–/– BMDCs are significantly resistant to LPS-induced apoptosis. Our results led us to investigate the role of HPK1^–/– BMDCs in tumor immunotherapy. Using a s.c. murine model of Lewis Lung Carcinoma, we found that HPK1^–/– BMDCs eliminate established s.c. Lewis Lung Carcinoma more efficiently than their WT counterpart. Our data reveal a novel role for HPK1 as a negative regulator of DC functions, identifying its potential as a molecular target for DC-based immunotherapy against cancers.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: Kennedy Institute of Rheumatology, Imperial College London; 65 Aspenlea Road London W6 8LH, U.K.

² Current address: Mount Sinai Cancer Institute, Department of Oncological Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, Ichan 15-75B, New York, NY 10029.

³ Address correspondence and reprint requests to Dr. Sansana Sawasdikosol, Mount Sinai School of Medicine, Mount Sinai Cancer Institute, Department of Oncological Sciences, 1425 Madison Avenue, Ichan 15-75B, New York, NY 10029. E-mail address: sansana.sawasdikosol{at}mssm.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; HPK1, hematopoietic progenitor kinase 1; WT, wild type; BMDC, bone marrow-derived DC; LLC, Lewis Lung Carcinoma.

⁵ The online version of this article contains supplementary material.

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