The nuclear orphan receptor NR2F6 as cancer immune checkpoint

Cancer comprises multi-factorial disorders and remains a major cause of mortality worldwide. So far, the mechanistic understanding of many acquired hallmarks of cancer is limited due to their biological complexity. Therefore, the precise characterization of as many aspects of cancer biology as possible will help to fight this frequently-incurable disease. Chronic inflammation has been shown, both experimentally and epidemiologically, to be a predisposition, or perhaps an inseparable aspect, in the pathogenesis of certain cancers. These findings imply a functional bridge between aberrant inflammation and the occurrence of tumors, a connection widely recognized but poorly understood. Nevertheless, the discovery of the strong association between aberrant inflammation and carcinogenesis has markedly changed our view of the pathogenesis of the clinically most prevalent types of cancer and thereby led to the concept of inflammation-associated neoplasia as an important area of research. On the other hand key metabolic pathways, local inflammation and immune cell invasion are cornerstones in host defense against carcinogenesis. Therefore, this proposed initiative aims to make a significant contribution to the rapidly advancing field of inflammation, cancer and immunity by elucidating the underlying mechanisms that shape the tumor microenvironment either to support or to prevent tumor initiation, progression or tumor immune surveillance. In particular, the defined and preselected molecular and cellular mechanisms of the PKC/NR2F6 axis determining the balance between immune surveillance and immune evasion of primary and metastatic tumors will be investigated. Major objectives of our extensive investigations within next 4 years are to provide important and clinically relevant information with a clear focus, why distinct forms of chronic inflammation predispose to tumor development while others are protective. This goes along with the investigation of defined immune effector function in association with specific cancer entities. Importantly, our proposed research project integrates both biological as well as translational as well as preclinical issues, aiming to bridge the gaps between the large spectrum of complementary scientific expertise, enabling technologies as well as various disease animal models and patient studies in order to address highly relevant (patho)mechanisms and to set the stage for an innovative therapeutic strategy of inflammation-related cancer.

Lay Summary: Orphan nuclear receptor NR2F6 as a promising new regulator and therapeutic target Cancer is a progressive disease that is influenced by both the tumor itself and the immune system. Nuclear receptors (NR) are also known to regulate both tumor and immune cells. In this research project, the research group of Prof. Gottfried Baier, Med. Univ. Innsbruck, intensively investigated the anti-inflammatory function of the immune cell-specific NR, nuclear receptor subfamily 2, group F, member 6 (NR2F6), aka: Ear2/COUP-TFIII, as a bona fide immune checkpoint of immune cell signaling networks in health and disease. New molecular and cellular processes of this NR2F6 signaling pathway were identified in detail and validated preclinically. In particular, the suppression of cancer immunity was identified as a fundamental process of malignant diseases. Until now, the NR2F6 signaling pathway has been largely neglected by global research. Between 1992 and 2023, there were only 82 publications on NR2F6 in PubMed. Thanks to the Innsbruck study, the role of NR2F6 as an immune checkpoint in effector T cells is now well documented. It was also investigated whether there is a specific role of tumor-specific NR2F6 in the biological context of tumorigenesis. Our investigations also showed a dual and tumor-promoting role of NR2F6 in immune and tumor cells - a new and very exciting concept. The specific role of tumor-derived NR2F6 in the biological context of tumorigenesis has not been investigated. One of our findings now describes for the first time a role of NR2F6 in the regulation of the immune defense of melanoma cells within the tumor. A high expression of NR2F6 in the tumors is associated with a particularly unfavorable survival rate. The function of NR2F6 also appears to be of great importance for an improved response to the cancer immunotherapies nivolumab and ipilimumab in melanoma. It has now been shown that the tumor's own NR2F6 function also appears to be highly relevant for activating and recruiting a suitable tumor-immune microenvironment network. Consistent with this reasoning, it is noteworthy that a combination of tumorigenic and immune cellular inhibition of the NR2F6 gene synergistically blocks tumor growth. So could NR2F6 be an excellent therapeutic target, especially in melanoma? Such a strategy for NR2F6 was proposed by the Innsbruck team some time ago. An approach that gains in importance in light of the groundbreaking discovery reported here and once again justifies the rapid development of systemic NR2F6 inhibitors. This is because such a systemic NR2F6 antagonist as an anti-cancer pharmacologic agent, once clinically available, would show therapeutic benefit both in melanoma cells and especially in CD8 T cells, thus achieving a synergistic therapeutic effect. This is indeed an important finding that should accelerate the implementation of NR2F6-targeted therapeutic strategies.