Plasticity of natural killer cells in cancer

• Applicant: Dr. Vikas Duhan, Ph.D.
• Subject Area: Immunology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433256315

Natural killer (NK) cells are known to exert direct anti-tumor activity and secrete an array of proteins that regulate immune responses in the tumor microenvironment. NK cells are a subset of the innate lymphoid cell 1 (ILC1) family. NK cells and ILC1s are closely related to each other as these cell types share many properties such as surface proteins, transcription factors and many cellular functions. Despite many similarities, NK cells are commonly found in secondary lymphoid organs whereas ILC1s are tissue resident and distributed in non-lymphoid organs such as liver, gut and adipose tissue. We have recently described both NK cells and ILC1-like cells (both intermediary CD49a+b+ and terminal CD49a+b–) in mouse tumors. While ILC2s and ILC3s were known to be highly plastic depending on their microenvironment stimuli, we and an independent group showed that TGF-β signaling converted NK cells into ILC1s. These reports determined that induced TGF-β signaling in NK cells during physiological conditions or in TGF-β rich tumor microenvironments promoted conversion of NK cells to ILC1s. While both NK cells and ILC1s produce IFN-γ and TNF, in tumors they do so at different ratios (NK cells have higher IFN-γ/TNF ratio), and whilst NK cells are specialized effector cells, ILC1-like cells appear to be pro-tumorigenic and have an angiogenesis promoting profile. This NK cell to ILC1 transition resulted in tumor progression and metastasis. Although these findings are established there open following questions in the field of NK cells and cancer immunology: 1) Which pathways other than TGF-β regulate NK cell plasticity and function in cancer control? 2) Is the transition between NK cells and ILC1 bidirectional? 3) What is the physiological relevance of NK-ILC1 plasticity in cancer? Previous studies showed that adenosine and prostaglandin E2 (PGE2) signaling dampen NK cell effector functions while type I interferon (IFN-I) signaling promotes NK cell activity in tumor microenvironment. However, the impact of these signaling pathways remains elusive for NK cell plasticity. Based on our preliminary data and hypothesis, we will investigate the cell intrinsic role of adenosine, PGE2 and IFN-I signaling on NK cell plasticity and bidirectionality, and pharmacologically target NK cell plasticity in different murine tumor models to understand their functional relevance to cancer development and progression. We will also investigate the NK-ILC1 transition phenomenon in human tumors.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Professor Dr. Mark Smyth, Ph.D.