Cancers are like uncontrolled pathogens. They multiply and spread up to the point of killing their host. Naturally our immune system protects us not only from pathogens but also from cancers. Indeed, cancer immunotherapy has been an effective therapy against many cancers. However, the underlying mechanisms in many cases are poorly understood. Type I interferon (IFN) and anti-tumor T cells are vital in controlling immunogenic tumors. IFN signaling in dendritic cells (DCs) is crucial for cross-priming of T cells against tumors. DCs mediates the immune recognition of tumors via cytosolic DNA sensing pathway and subsequent production of IFN from the DCs. It is unclear, however, how immunogenic tumors induces IFN production from DCs through the cytosolic DNA sens- ing pathway and how IFN signaling in DCs is necessary for the cross-priming of T cells. While studying host- pathogen interactions, we discovered a novel function of autophagy proteins that can provide answers to these questions. Autophagy is an evolutionarily conserved cellular pathway that encloses cytoplasmic materials in membrane-bound autophagosomes and delivers them to the lysosome for degradation. The autophagosomes form from endomembranes reorganized via the ubiquitin-like conjugation system of the autophagy pathway. We found that the conjugation system plays another essential role in the disintegration of intracellular vacuoles con- taining pathogens by tagging the vacuoles with ubiquitin-like LC3 (microtubule associated protein 1 light chain 3). The membrane bound LC3s function as molecular beacons to recruit IFN-inducible GTPases, and the re- cruited GTPases disrupt the vacuoles. As a result, the pathogens hidden inside the vacuole are exposed to the cytoplasm. We hypothesize that the same LC3 conjugation system in DCs opens up phagocytic vacuoles con- taining tumor cell DNAs and antigens by recruiting the IFN-inducible GTPases to the vacuoles. Subsequent release of the contents to the cytoplasm of the DCs will lead to cytosolic DNA sensing-dependent IFN production (positive amplification of IFN signal) and the cross-priming of cytotoxic T cells against the tumor cells. To test this hypothesis, we will investigate the role of the relevant autophagy genes and the IFN-inducible GTPases in DCs for the production and amplification of IFNs, the cross-priming of cytotoxic T cells against tumor antigens, and the control of immunogenic tumors in vivo. Successful completion of the proposed study will lead to a better understanding of innate and adaptive immune recognition of tumors. Such results are expected to have positive impact on human health because it is probable that the identified immune regulatory mechanism will provide new targets for therapeutic interventions of cancers. In addition, it is likely that the result will enhance our under- standing of how the immune system controls cytosolic vacuoles containing materials of interest (e.g. pathogens, tumors, etc.), thereby fundamentally advancing the fields of cancer biology, immunology and cell biology. Fur- ther, the targeting mechanism may be utilized for other process, like controlled drug delivery. In essence, this is a high-risk/high-reward project.

Public Health Relevance

This proposal aims to elucidate a basic immune mechanism that detect tumors, which can be directly translated to anti-tumor immune therapies. The planned research is based on a novel non-canonical/non-degradative function of autophagy proteins for disruption of pathogen-containing vacuoles and release of the resident pathogen to the cytoplasm. Applying this novel concept of host-pathogen interaction to the unknown area of host-tumor interaction is an innovative approach that has the potential to impact broadly on biomedical research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2CA225208-01
Application #
9350598
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Howcroft, Thomas K
Project Start
2017-09-01
Project End
2022-06-30
Budget Start
2017-09-01
Budget End
2022-06-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Brown, Hailey M; Biering, Scott B; Zhu, Allen et al. (2018) Demarcation of Viral Shelters Results in Destruction by Membranolytic GTPases: Antiviral Function of Autophagy Proteins and Interferon-Inducible GTPases. Bioessays 40:e1700231
Lee, Ji-Hye; Park, Beom Seok; Han, Kang R et al. (2018) Insight Into the Interaction Between RNA Polymerase and VPg for Murine Norovirus Replication. Front Microbiol 9:1466
Coers, Jörn; Brown, Hailey M; Hwang, Seungmin et al. (2018) Partners in anti-crime: how interferon-inducible GTPases and autophagy proteins team up in cell-intrinsic host defense. Curr Opin Immunol 54:93-101
Kang, Soowon; Brown, Hailey M; Hwang, Seungmin (2018) Direct Antiviral Mechanisms of Interferon-Gamma. Immune Netw 18:e33