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

Abstract

Lung cancer is the leading cause of cancerrelated 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 eVect 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 hematopoieticspeciWc 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-inWltrating lymphocytes (TILs) and T-cell transfer into T cell-deWcient mice revealed that tumor rejection is T cell mediated. Further analysis demonstrated that this may be signiWcantly 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.

Inhibited expression of hematopoietic progenitor kinase 1 associated with loss of jumonji domain containing 3 promoter binding contributes to autoimmunity in systemic lupus erythematosus

“…We thus speculated that increased H3K27me3 levels may repress HPK1 expression in SLE CD4þ T cells. Since HPK1 is a negative regulator of TCR signaling and T cell-mediated immune responses [40,43], we hypothesized that the loss of HPK1 may play a causative role in the pathogenesis of SLE. To understand the specific function of HPK1 in SLE CD4þ T cells and the mechanisms that regulate HPK1 expression, we first determined that HPK1 protein and mRNA levels were both significantly reduced in CD4þ T cells of patients with SLE.…”

“…It belongs to the germinal center kinase (GCK) family and can be activated by a variety of signal stimuli, such as epidermal growth factor (EGF) [25], prostaglandin E 2 (PGE 2 ) [26], transforming growth factor-b (TGF-b) [27], erythropoietin (EPO) [28], and TCR and BCR stimulation [29e32]. It is also involved in various cellular events, such as MAPK [33e36], NF-kB [29,37e39] and cytokine signalings [28,40,41], as well as cellular proliferation and apoptosis [31,42e44]. In addition, HPK1 negatively regulates TCR signaling and T cell-mediated immune responses [40,43].…”

“…It is also involved in various cellular events, such as MAPK [33e36], NF-kB [29,37e39] and cytokine signalings [28,40,41], as well as cellular proliferation and apoptosis [31,42e44]. In addition, HPK1 negatively regulates TCR signaling and T cell-mediated immune responses [40,43]. Shui et al found that HPK1 À/À mice T cells become hyperproliferative in response to stimulation with anti-CD3 and anti-CD28 antibodies, and that these cells can produce more proinflammatory cytokines when immunized with T cell-dependent antigens.…”

Hematopoietic progenitor kinase 1 (HPK1) is required for LFA-1–mediated neutrophil recruitment during the acute inflammatory response

“…29 All animal experiments were institutionally approved by Regierung von Oberbayern, Munich, Germany.…”

HPK1 competes with ADAP for SLP‐76 binding and via Rap1 negatively affects T‐cell adhesion

“…S1) were generated in the C57Bl/6 background [29] and used at 6 wk or more with age-matched controls. All animal experiments were approved by the Animal Experimentation Committee of the Federal Ministry of Nature, Environment and Consumer Protection of North Rhine Westphalia, permit number 50.0835.1.0 (G89/2004).…”