Treatments that activate immune responses against tumor cells have revolutionized cancer therapeutics. These treatments are the culmination of decades of studies into how the immune system recognizes and eliminates cancer, but more research is necessary to find additional therapeutic targets and improve current ones. Natural Killer (NK) cells are one type of immune cell with potent anti-tumor activities. NK cells delineate cancer cells from normal tissue using germline-encoded cell surface receptors that recognize molecules on transformed cells but not healthy cells. NK cells eliminate tumors by secreting cytotoxic granules and powerful anti-tumor cytokines. Because many therapies to boost NK responses are in clinical development, it is crucial to thoroughly explore the mechanisms that regulate NK activity against tumors. A recent study in our laboratory provided evidence that tumor-infiltrating myeloid cells persistently stimulate NK cells through the NK immunoreceptor NKG2D. This persistent stimulation causes NK cells to be less active and unable to kill cancer cells, allowing the tumor to evade NK recognition. This desensitization is driven by the NKG2D ligand (NKG2D-L) RAE-1? expressed on tumor-infiltrating macrophages and monocytes. Preliminary data suggest that myeloid RAE-1? expression is caused by the cytokine MCSF, produced by tumor cells. Thus, tumors may facilitate their own growth using a multicellular axis to circumvent NK cell-mediated immunosurveillance. This application seeks to further explore the molecular underpinnings of these findings, and to test whether interrupting NKG2D/RAE-1? interactions between NK cells and myeloid cells can relieve this desensitization and promote tumor rejection.
In Aim 1, blocking antibodies against MCSF, lentiviral overexpression of MCSF, and Cas9-mediated knockout of the MCSF gene in tumor cells will be used to determine whether tumor-derived MCSF promotes RAE-1? expression on tumor-infiltrating myeloid cells in transplanted and autochthonous tumor models. The signaling pathways responsible for RAE-1? induction by MCSF will be explored by examining whether PI3K, downstream of MCSF stimulation, regulates RAE-1? in macrophages. Overexpression and knock-down strategies will be used to modulate PI3K signals to examine the contribution of this pathway to RAE-1? induction. Finally, I will determine whether human MCSF can stimulate NKG2D-L induction on peripheral blood monocytes, and examine human NKG2D-L expression on myeloid cells infiltrating tumors in humanized mice.
In Aim 2, blocking antibodies against MCSF and RAE-1?, genetic ablation of RAE-1?, and macrophage depletion will be used to determine whether interrupting the MCSF/RAE-1?/NKG2D desensitization axis, alone or in combination with other therapies that activate NK cells, can promote rejection of tumors expressing ligands for NKG2D and other NK receptors. We hypothesize that MCSF- and RAE-1?-dependent NK desensitization is a common feature of tumors and a potentially worthwhile target for cancer therapy.

Public Health Relevance

Natural Killer (NK) cells are immune cells that can recognize and kill cancer cells, and recent therapies that seek to boost NK cell activity against tumors have shown clinical promise. This research project seeks to investigate a novel mechanism that tumor cells use to escape destruction by NK cells, and to explore the feasibility of interrupting this escape mechanism in cancer patients to restore the capacity of NK cells to eliminate tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA203262-02
Application #
9252223
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perkins, Susan N
Project Start
2016-04-01
Project End
2017-12-31
Budget Start
2017-04-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Thompson, Thornton W; Jackson, Benjamin T; Li, P Jonathan et al. (2018) Tumor-derived CSF-1 induces the NKG2D ligand RAE-1? on tumor-infiltrating macrophages. Elife 7:
Thompson, Thornton W; Kim, Alexander Byungsuk; Li, P Jonathan et al. (2017) Endothelial cells express NKG2D ligands and desensitize antitumor NK responses. Elife 6: