PROJECT SUMMARY/ABSTRACT
Despite breaking advances in melanoma treatment such as adoptive cell transfer and immune checkpoint
blockade, the clinical outcomes remain unsatisfactory due to various factors that limit the efficacy of the
therapies. To meet these challenges in immunotherapy for solid tumors, this project aims to define
eukaryotic elongation factor-2 kinase (eEF-2K) as a novel and effective immune-modulatory target that can
be exploited to significantly improve effectiveness of the current cancer immunotherapy. eEF-2K belongs to
the family of atypical a-kinases and is an evolutionarily conserved regulator of protein synthesis, a molecular
process that affects energy metabolism. This kinase phosphorylates eEF-2, a 100-kDa protein that
promotes ribosomal translocation from the A to P-site, the reaction that induces movement of mRNA along
the ribosome during translation. Phosphorylated eEF2 is unable to catalyze ribosomal translocation, thereby
inhibiting peptide elongation. Our preliminary studies strongly suggest that eEF-2K is an as-yet-
unappreciated but critical regulator of antitumor immunity and that integrative targeting of this kinase may
beneficially maximize the potency of immunotherapeutic intervention against melanoma, one of the most
aggressive and fatal neoplasms responsible for over 80% of skin cancer-related deaths. Building on our
preliminary observations that eEF-2K is not only highly expressed in melanoma cells and patient specimens
and contributes to poor therapeutic outcomes, but is also abundantly expressed in immune cells such as T
cells and regulates their functional activity, we propose to test the central hypothesis that eEF-2K modulates
antitumor immunity via its regulatory roles in both tumor cells and tumor-reactive immune cells, and
integrative targeting of eEF-2K could be exploited as an innovative therapeutic strategy for treatment of
melanoma. Through comprehensive cellular, molecular, and pre-clinical studies, this multiple PIs’ project will
pursue the following highly related and interactive aims: (1) Determine the role and in-depth mechanism of
eEF-2K in immune evasion; (2) Define the role of eEF-2K as a regulator of tumor-reactive immune cells; (3)
Evaluate the antitumor efficacy of the eEF-2K-based and integrative targeted therapy. We have established
the humanized mouse (NOD-scid IL2Rgnull) melanoma models as well as murine syngeneic melanoma
systems for this research and are well poised to accomplish the above objectives. This research is
innovative and significant because successful completion of this project would not only reveal eEF-2K as a
novel and effective immuno-modulatory target for overcoming tumor immune-resistance as well as
regulating immune cell functions, but also provide new therapeutic opportunities to substantially improve
immunotherapy for advanced treatment-refractory melanoma through the eEF-2K-based integrative-
targeted approach.