Critical role of kinase activity of hematopoietic progenitor kinase 1 in anti-tumor immune surveillance

Abstract

Immunotherapy has fundamentally changed the landscape of cancer treatment. Despite the encouraging results with the checkpoint modulators, response rates vary widely across tumor types, with a majority of patients exhibiting either primary resistance without a significant initial response to treatment or acquired resistance with subsequent disease progression. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cell linages and serves as a negative regulator in T cells and dendritic cells (DC). While HPK1 gene knockout (KO) studies suggest its role in anti-tumor immune responses, the involvement of kinase activity and thereof its therapeutic potential remain unknown. To investigate the potential of pharmacological intervention using inhibitors of HPK1, we generated HPK1 kinase dead (KD) mice which carry a single loss-of—function point mutation in the kinase domain and interrogated the role of kinase activity in immune cells in the context of suppressive factors or the tumor microenvironment (TME). Our data provide novel findings that HKP1 kinase activity is critical in conferring suppressive functions of HPK1 in a wide range of immune cells including CD4+, CD8+, DC, NK to Tregs, and inactivation of kinase domain was sufficient to elicit robust anti-tumor immune responses. These data support the concept that an HPK1 small molecule kinase inhibitor could serve as a novel agent to provide additional benefit in combination with existing immunotherapies, particularly to overcome resistance to current treatment regimens.

A perspective on HPK1 as a novel immuno-oncology drug target

“…Ovalbumin immunized HPK1 -/-BMDCs could elicit a greater proliferative response of adoptively transferred OTI T cells than their wild type counterpart. This finding is consistent with the report of an elevated OTI proliferative response to enhanced antigen presentation by ovalbumin peptide-pulsed catalytically-inactive K46M HPK1 BMDCs in vitro, which suggests the enhanced antigen presentation is dependent of the HPK1 kinase activity (Liu et al, 2019). In addition to possessing a superior ability to prime T cells, another mechanism might be enhanced antigen presentation in the tumor microenvironment (TME).…”

“…Some immune-edited cancers that downregulate their MHC Class I molecule as part of their immune evasion tactic may be subjected to lysis by natural killer (NK) cells that become activated through the absence of inhibitory signals normally provided the MHC Class I molecules or by the presence of stress markers MIC-A or MIC-B on cancer cells (Long et al, 2013;Campbell and Hasegawa, 2013). In this regard, NK cells isolated from catalytically inactive K46M HPK1 mutant mice were shown to possess increased cytotoxic activity in vitro against YAC-1, a NK-sensitive murine lymphoma, when compared to the activity of wild type NK cells (Liu et al, 2019). If such increased cytotoxic activity levels were shown to occur in the K46M or K46E HPK1 tumor-bearing hosts, the elevated NK-mediated tumor lysis might increase the amount of neoantigen present for dendritic cells to cross-present to T cells in vivo.…”

“…In fact, Hernandez et al had argued that the ability of the adoptive transferred catalytically-inactive K46E HPK1 mutant T cells to acquire an enhanced activated phenotype in vivo through priming by the host's wild type dendritic cells suggests that disruption of HPK1-regulated kinase activity in T cells is sufficient to confer the enhanced tumor immunity phenotype independent of the contribution from enhanced antigen presentation by the kinase inactive K46E HPK1 dendritic cells (Hernandez et al, 2018). However, since dendritic cells from neither the K46E HPK1 mice used by Hernandez et al nor the dendritic cells from the K46M HPK1 mice used by Liu et al were assessed for their ability to function in a cancer vaccine the way analogous HPK1 -/-BMDCs were assessed (Liu et al, 2019;Hernandez et al, 2018), the relevance of HPK1 kinase activity in the regulation of cancer neoantigen presentation in the TME warrants further investigation.…”

Revolutionizing the landscape of colorectal cancer treatment: The potential role of immune checkpoint inhibitors

“…The MAP4K serine/threonine kinase, HPK-1 was highlighted as a modulator of the tumor microenvironment via acting as a suppressor for the activity of T cells (CD4+, CD8+), DCs and natural killer cells (NKs). 93,94 It is mainly expressed by certain subsets of hematopoietic cells. 94 Furthermore, the antitumor immunity was reported to be boosted in MC38 (colon cancer) and GL261 (glioma) syngeneic mice with defective HPK-1.…”

Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

“…For instance, studies using a model of autoimmune encephalomyelitis suggest that HPK1 negatively regulates T-cell activation and function [82]. Similarly, in in vivo models of lung cancer, the loss of HPK1 enhances the effector function of cytotoxic T-cells [83]. However, the translational relevance of these findings is unclear at this time.…”