The immune system surveys the skin and other barrier tissues such as lung and gut, but mechanisms for failed immunity in the periphery that lead to cancer or autoimmune diseases are unknown. The dendritic cell (DC) is a specialized immune sentinel that directs T cells to tolerance or immunity. DC comprise a rich network in skin consisting of several different populations, but are understudied, leaving a major gap in therapeutic intervention. We have identified distinct properties for DC in skin that relay information by migrating out to the draining lymph node (LN). We find during inflammation skin migratory DC may direct T cells to tolerance by unknown mechanisms, counter-regulating and controlling immunity. These cells are uniquely genetically programed in humans and in mouse to dampen immunity with a high expression of shared tolerance genes, including some genes such as PD-L1 that have been successfully targeted in the clinic for peripheral tissue cancers including melanoma skin cancer, colorectal cancer and lung cancer. We hypothesize homeostatic programming of skin DC leads to failed immune priming leading to impaired early detection of skin cancers. We find these pathways are of great importance as therapeutic targets to promote self-tolerance (such as during autoimmune disease) or to block tolerance (to improve immunity during cancer). Because these mechanisms are distinct they can be combined with current modalities for patients in immunotherapy of skin cancer, vaccine science, and inflammatory skin disease. In 2 discrete aims, this application will address programmatic conditioning of skin DCs and the unique cellular mechanisms by which they promote immune tolerance in both mice and humans, examining consequences during immune priming and early skin cancer growth.

Public Health Relevance

We address a fundamental gap in our understanding of human immunology- how the immune system in the skin - a primary defense barrier, is uniquely conditioned. We identified that critical immune cells called dendritic cells (DC), are programmed to be more tolerant after traveling through the skin. This application tests how the activity of these cells may lead to failed detection of skin cancer and immune priming.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR070234-04
Application #
9542647
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2018-04-11
Project End
2021-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Dermatology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Nirschl, Christopher J; Suárez-Fariñas, Mayte; Izar, Benjamin et al. (2017) IFN?-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment. Cell 170:127-141.e15
Devi, K Sanjana P; Anandasabapathy, Niroshana (2017) The origin of DCs and capacity for immunologic tolerance in central and peripheral tissues. Semin Immunopathol 39:137-152
Vardam, Trupti; Anandasabapathy, Niroshana (2017) Langerhans Cells Orchestrate TFH-Dependent Humoral Immunity. J Invest Dermatol 137:1826-1828
Morse, Kaitlyn; Kimizuka, Yoshifumi; Chan, Megan P K et al. (2017) Near-Infrared 1064 nm Laser Modulates Migratory Dendritic Cells To Augment the Immune Response to Intradermal Influenza Vaccine. J Immunol 199:1319-1332