Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2-mediated suppression of the anti-tumor immune response.
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 (PGE(2)) present in the tumor environment. The effect of PGE(2) 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 PGE(2) 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 PGE(2)-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 PGE(2)-mediated suppression of T-cell proliferation, IL-2 production, and apoptosis. We conclude that PGE(2) utilizes HPK1 to suppress T cell-mediated anti-tumor responses.
Alzabin
Saba
S
NYU Cancer Institute, Department of Medicine, New York University School of Medicine, New York, 10016, USA.
Pyarajan
Saiju
S
Yee
Herman
H
Kiefer
Friedemann
F
Suzuki
Akira
A
Burakoff
Steven
S
Sawasdikosol
Sansana
S
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology*; D015232:Dinoprostone / Q000502:physiology*; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D019139:Tumor Escape
C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases; D015232:Dinoprostone