In the field of tumor immunology, while the generation and maintenance of anti-tumor CD8 T cell memory responses are considered crucial for the long-term host survival, the basic tenets of memory formation remain to be established. We propose to study and manipulate the CD8 T cell NKG2D/DAP10 ribosomal protein S6 (rpS6) pathway as a means to generate durable and protective anti-tumor immunity. The scientific premise of this study is derived from our work demonstrating that NKG2D signaling provides CD8 T cells with pro-memory signals. We hypothesize that NKG2D, through finely tuned DAP10PI3K/Grb2 signaling (as NKG2D cannot signal by itself, instead uses DAP10PI3K/Grb2 as signaling adaptor), activates rpS6 resulting in the development of functionally capable CD8 memory T cells. This proposal will define the underlying players required for rpS6 phosphorylation downstream of NKG2D/DAP10 and its implications in the development of immunological memory against tumors including TRM cells. Here we will conduct proof-of-concept tests utilizing human and mouse tumors, with the intention of preparing for a clinical trial. SA1: TO DETERMINE THE MOLECULAR CONTRIBUTORS OF NKG2D-DAP10 INDUCED PHOSPHORYLATION OF rpS6 SA2. TO DETERMINE THE ROLE OF NKG2D/DAP10PI3K/GRB2 IN THE DEVELOPMENT OF TRADITIONAL MEMORY RESPONSES AND SKIN TRM CELLS AGAINST MELANOMA. SA3. TO EVALUATE THE THERAPEUTIC POTENTIAL OF MANIPULATING THE DAP10/rpS6 PATHWAY IN CD8 T CELLS