Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2-mediated suppression of the anti-tumor immune response

Saba Alzabin, Saiju Pyarajan, Herman Yee, Friedemann Kiefer, Akira Suzuki, Steven Burakoff, Sansana Sawasdikosol

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Lung cancer is the leading cause of cancer-related mortality in the world, resulting in over a million deaths each year. Non-small cell lung cancers (NSCLCs) are characterized by a poor immunogenic response, which may be the result of immunosuppressive factors such as prostaglandin E2 (PGE2) present in the tumor environment. The effect of PGE2 in the suppression of anti-tumor immunity and its promotion of tumor survival has been established for over three decades, but with limited mechanistic understanding. We have previously reported that PGE2 activates hematopoietic progenitor kinase 1 (HPK1), a hematopoietic-specific kinase known to negatively regulate T-cell receptor signaling. Here, we report that mice genetically lacking HPK1 resist the growth of PGE2-producing Lewis lung carcinoma (LLC). The presence of tumor-infiltrating lymphocytes (TILs) and T-cell transfer into T cell-deficient mice revealed that tumor rejection is T cell mediated. Further analysis demonstrated that this may be significantly due to the ability of HPK1 -/- T cells to withstand PGE2-mediated suppression of T-cell proliferation, IL-2 production, and apoptosis. We conclude that PGE2 utilizes HPK1 to suppress T cell-mediated anti-tumor responses.

Original languageEnglish
Pages (from-to)419-429
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume59
Issue number3
DOIs
StatePublished - Mar 2010

Keywords

  • Immunosuppression
  • Lung cancer
  • Prostaglandin E2
  • T cell
  • Tumor immunology

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