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

Public Health Relevance

In this study, we present preliminary data indicating that NKG2D signaling on CD8 T cells extends beyond the known canonical function (facilitating target recognition and favored killing), by providing pro-memory signals. This proposal will define the underlying players required for rpS6 phosphorylation downstream of NKG2D/DAP10 stimulation and its implications in the development of anti-tumor immunity and TRM cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA250514-02
Application #
10120659
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2020-03-05
Project End
2025-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Loyola University Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153