Victoria Klepsch
Medical University Innsbruck, Austria
Title: Beyond CTLA-4 and PD-1: Orphan nuclear receptor NR2F6 as T-cell signaling switch and emerging target in cancer immunotherapy
Biography
Biography: Victoria Klepsch
Abstract
Modulation of the immune system for the treatment of primary and metastatic tumors in cancer patients has been a goal for many decades. Very recently, blockade of immune checkpoints CTLA-4 and PD-1 has emerged as promising cancer immune therapies. Even though encouraging, there is an unmet medical need as still only a very limited number of patients respond to and are potentially cured by these therapies. In contrast to cell surface checkpoints, there are cancer therapeutic targets that are located inside the immune cells and are amenable to pharmacological modulation. Based on our published and unpublished findings that genetically NR2F6-deficient mice are able to immunologically reject otherwise lethal tumor burdens; we have identified and preclinically validated the orphan nuclear receptor NR2F6 (nuclear receptor subfamily 2, group F, member 6; alias Ear2 and COUP-TFIII) as a bona fide immune checkpoint. We could show that genetic ablation of NR2F6 significantly improves survival in the murine transgenic TRAMP prostate cancer model. Furthermore, NR2F6-/- mice spontaneously reject implanted tumors and develop host-protective immunological memory against tumor re-challenge. This is paralleled by increased frequencies of both CD4+ and CD8+ T-cells and higher expression levels of interleukin-2 and interferon-ï§ at the tumor site. This defines NR2F6 as an intracellular and potentially also druggable immune checkpoint, where the presence of NR2F6 limits effector T-cell activation within the tumor microenvironment governing the amplitude of anti-cancer immunity, representing a promising avenue for development of alternative immune checkpoint inhibition treatment regimens.
