Cancer immunotherapy attempts to boost the body?s own defense mechanism ? the immune system ? to kill cancer cells and defeat cancer. Immunotherapy with T cell checkpoint inhibitors is promising to revolutionize cancer therapy. However, a major limitation of these therapies is that they are effective in only a subset of patients. Recent evidence suggests that enhanced T cell infiltration in the tumor is a predictive marker of positive response to T cell checkpoint inhibitors. Thus, failure to respond to T cell checkpoint inhibitors may correspond to a defect in the ability of the innate immune system to effectively engage adaptive anti-tumor immune response. In mice, we have identified and disabled a novel immune checkpoint mechanism, a cellular protein named MERTK, that is found in innate immune cells ? the body?s first line of immune defense. MERTK limits the extent to which innate immune cells can get activated, which in turn controls how much the overall immune response would be. We have also detected the presence of MERTK in tumor-associated innate immune cells in human samples. In mouse models of cancer, genetic ablation of Mertk results in dramatic prevention of cancer growth. We propose to (i) use mouse models of cancers to investigate the mechanism/s by which loss of MERTK function improves anti-tumor immunity, (ii) test if acute ablation of Mertk in established tumors and the inactivation of its kinase activity are sufficient to overcome the failure to trigger anti- tumor T cell responses and restrict tumor growth, and (iii) to investigate the association between MERTK activation and the resistance to T cell checkpoint inhibitors in patients. Through these studies, we will better understand how the immune system can fight cancer when the MERTK brake is removed, obtain proof-of- concept for therapeutic use of drugs that would inhibit MERTK, and develop a predictive biomarker panel for the identification of a subset of patients that are likely to respond to MERTK inhibitors. In summary, our proposed studies can potentially identify a novel target for cancer immunotherapy that by itself, or in combination with FDA-approved checkpoint inhibitors or molecular targeted therapies, could significantly increase the percentage of patients that show objective response to anti-cancer therapy.

Public Health Relevance

As cancer threatens to become the number one cause of mortality in this nation, immune checkpoint inhibitors, a new class of immunotherapy agents, have emerged as a powerful weapon against this disease. Immune checkpoint inhibitors remove naturally occurring brakes in immune cells, thereby improving the ability of the body?s own immune system to recognize and destroy cancer cells. Here we propose to target a novel immune checkpoint that is present within innate immune cells, our first line of immune defense, and to understand the molecular processes that enhance the anti-cancer immune response upon inhibition its function as well as its association with human disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA212376-01A1
Application #
9333684
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2017-03-01
Project End
2022-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
$455,406
Indirect Cost
$183,522
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Spadaro, Olga; Camell, Christina D; Bosurgi, Lidia et al. (2017) IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge. Cell Rep 19:225-234
Bosurgi, Lidia; Hughes, Lindsey D; Rothlin, Carla V et al. (2017) Death begets a new beginning. Immunol Rev 280:8-25
de Kouchkovsky, Dimitri A; Ghosh, Sourav; Rothlin, Carla V (2017) Negative Regulation of Type 2 Immunity. Trends Immunol 38:154-167
Hughes, Lindsey D; Bosurgi, Lidia; Ghosh, Sourav et al. (2017) Chronicles of Cell Death Foretold: Specificities in the Mechanism of Disposal. Front Immunol 8:1743
Bosurgi, Lidia; Cao, Y Grace; Cabeza-Cabrerizo, Mar et al. (2017) Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science 356:1072-1076