class="head no_bottom_margin" id="sec1title">IntroductionAdaptive immunity together with innate effector immune cells is established to efficiently control malignant cells. The importance of T cells for tumor cell elimination is underscored by the observation that tumor infiltration by T cells represents a valuable prognostic marker in different human cancer types (; reviewed in ). Residual T cell reactivity against malignant cells is limited by various components of immune evasion, such as local accumulation of immunosuppressive cell types within the tumor microenvironment. Together this favors tumor escape from the immune system instead of immune-mediated cancer cell elimination (for review, see ). Consistently, interleukin 2 (IL-2) and interferon γ (IFN-γ) are both additional key prognostic indicators mirroring a protective anti-tumor immune response in humans. High IL-2 levels thereby favor CD8+ T cell effector functions (). High IFN-γ directly modulates both cancer biology (e.g., by inducing tumor cell senescence) () and induces an immune contexture favoring continuous tumor cell elimination, a concept coined “cancer immune surveillance” ().Manipulating the immune system to harness anti-tumor immune responses for the treatment of cancer patients has been a major goal for many decades. Promising novel therapeutic advances blocking immune system inhibitory pathways, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1)/PD-1 ligand (PD-L1), are referred to as “immune checkpoints” (i.e., inhibitory signaling intermediates that control the duration and amplitude of physiological immune responses) are successful entering into clinics (). In addition, adoptive T cell transfer therapy or vaccination approaches are now also providing more encouraging results, especially when combined with cytokines or the above mentioned immune checkpoint-antagonizing antibodies (). Even though these approaches are exciting, there is an unmet medical need, as still only a limited number of patients response to and even less patients are potentially cured by these approaches. Thus, there is a high scientific interest to explore novel cancer immunotherapeutic approaches with the ultimate goal to further strengthen the patient’s immune system.Notably, mechanistic processes that support immune-mediated tissue destruction appear to be strikingly analogous in autoimmunity and cancer. We previously demonstrated that the nuclear receptor subfamily 2, group F, member 6 (NR2F6; also called COUP-TFIII or Ear2) represents an important gatekeeper of antigen receptor-induced cytokine response thresholds of pro-inflammatory CD4+ Th17 lymphocytes (). In these autoimmunity-promoting Th17 cells, NR2F6 directly antagonizes the binding of the transcription factors NFAT and, particularly, retinoic acid receptor-related orphan receptor-γ-t (RORc) to the Il17 cytokine locus (), thereby reducing central nervous system inflammation. Here, we employed various types of transplantable and spontaneous tumor models to define the role of NR2F6 in tumor immunology. Using these model systems, we provide strong experimental evidence that genetic deletion of Nr2f6 is both necessary and sufficient to induce host-protective immune rejection of cancer. Nr2f6 deficiency leads to augmented intratumoral effector CD4+ and CD8+ T cell infiltration and strongly enhances local production of IL-2, IFN-γ, and tumor necrosis factor-α (TNF-α), thereby forming an immune environment that allows strong anti-tumor T cell responses in tumor-bearing mice.
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