Targeting the immunosuppressive adenosine-axis to overcome T-cell γc cytokine signaling blockade and enhance antitumor immunity in hepatocellular carcinoma

University Of Texas El Paso, El Paso TX

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Abstract

ABSTRACT Advanced hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer worldwide, yet patient responses to current immune checkpoint inhibitors (ICIs) remain unsatisfactory, highlighting the urgent need for improved therapies. A key contributor to immune resistance in HCC is the tumor microenvironment (TME), which is enriched with immunosuppressive metabolites such as adenosine. Our preliminary gene expression analyses reveal a significant upregulation of crucial adenosine pathway molecules, 5’-ectonucleotidase (CD73) and adenosine A2A receptor (A2AR), which correlate with poor patient outcomes. Moreover, immune profiling across various cancer types indicates adenosine-mediated T-cell suppression in the TME. Notably, the treatment of adenosine pathway inhibitors has been shown to enhance the T cell cytotoxicity against HCC cells. Our prior reports and preliminary findings suggest that elevated adenosine suppresses T-cell activation by inhibiting IL-2 signaling, possibly via the PKA pathway and the CD45-CD26 complex, revealing a dual mechanism for further exploration. Altered expressions of adenosine deaminase (ADA) and ADA binding protein (CD26) have also been reported in HCC tissues. These findings further position adenosine as a central mediator in multiple immunosuppressive pathways promoting tumor immune resistance in HCC, presenting a promising network for pharmacological modulations to improve immunotherapy efficacy. We hypothesize that adenosine-driven blockade of the γc/JAK3 cytokine family through the A2AR-PKA and CD45 pathways, promotes T cell inhibition and fosters an immunosuppressive TME, thus providing a promising opportunity to enhance antitumor immunity in HCC. This study focuses on exploring the potential of adenosine pathway molecules as therapeutic targets to enhance antitumor immunity in HCC. Specifically, we propose to 1) Characterize the A2AR/PKA-mediated uncoupling of γc networks through JAK3 serine phosphorylation and assess pharmacological strategies to restore γc/JAK3 signaling, countering adenosine-driven immunosuppression by screening blockade of PKA-targeted JAK3 inhibition. 2) Elucidate the CD45-mediated negative regulation of γc/JAK3 signaling by exploring the role of ADA-bound CD26 in adenosine-driven suppressive signaling. 3) Reverse the immunosuppressive TME of HCC and enhance ICIs′ antitumor efficacy by targeting the adenosine pathway and using PKA inhibitors. Collectively, the work will advance our understanding of how adenosine disrupts critical γc signaling networks in HCC and identify novel therapeutic targets to protect γc/JAK3 signaling from adenosine-mediated silencing. The pharmacological intervention of the adenosine axis offers a transformative approach to overcoming immunosuppression and enhancing the clinical efficacy of ICIs in HCC. For the first time, we will evaluate the potential of PKA inhibitors as immunomodulators for HCC with broader implications for other cancers exhibiting aberrant adenosine signaling.