Cancer immunotherapy, using regimens called immune checkpoint blockade (ICB) or personalized chimeric antigen receptor-engineered T cell immunotherapy (CAR-T), has become an innovative therapeutic pillar in oncology. Although cancer immunotherapy has definitely changed the way cancer is treated, a significant proportion of patients still fail to respond to, and even fewer are cured by, these current clinical strategies. Therefore, additional therapeutic target protein candidates suitable for the boosting of antitumor effector responses need to be identified. In my ERC project "HOPE", we are investigating the unique potential of the orphan intracellular receptor NR2F6 (nuclear receptor subfamily 2 group F member 6) and its effector pathway in T cells as an emerging alternative target for cancer immunotherapy to significantly increase response rates in e.g. NSCLC lung cancer patients.
We validated NR2F6 as a lege artis immune checkpoint using germline gene ablation and CRISPR/Cas9-mediated acute gene mutagenesis. Thus, especially in combination with ICB and CAR-T therapy regimens, targeting this nuclear receptor appears to be a strategy for improving antitumor immunotherapy responses. Taken together, our current preclinical experimental knowledge may be a promising and innovative perspective for human immunotherapy in the near future for the enhancement of immune system responses.
Why is the alternative and druggable immune checkpoint NR2F6 important?
NR2F6 is a recently discovered cancer immune checkpoint protein. It is found at particularly high levels in effector T cells that have infiltrated solid tumours. Consistent with this observation, genetic NR2F6 inhibition experiments have shown encouragingly strong improvements in T cell responses using both human PBMC in vitro and preclinical cancer therapy models in vivo. Investigation of Nr2f6 inhibition in mice using ex vivo CRISPR/Cas9-mediated gene ablation of Nr2f6 in T cells prior to therapeutic cell therapy, particularly in conjunction with ICB therapy, greatly improved the outcome of therapeutic anti-cancer responses.
NR2F6 may turn out to be an emerging and most suitable next-generation sensitiser target for improving T cell efficacy and subsequently immunotherapeutic outcome, thereby increasing the percentage of cancer patients responding to therapy, based on the current thinking that the most successful immuno-oncology concepts need to be used as combinatorial therapies.
Of particular note, our study targeting NR2F6 in mice in combination with ICB treatment showed no exacerbated signs of immune related adverse effects (irAE) over a three month follow-up period. When compared directly with untreated mice, there were no significant differences in immune cell infiltration, weight loss or colon length in mice with Nr2f6 deficiency. Our findings suggest that NR2F6 might be a highly localized immune checkpoint at the tumor site and that, subsequently, Nr2f6 inhibition boosts only a locally restricted antitumor effector T cell response with fewer systemic IrAE.
Indeed, NR2F6-targeting regimens are currently being investigated in research and development laboratories around the world. At the end of the day, we "HOPE" (as our ERC project acronym already suggested) that this NR2F6-centered alternative therapeutic approach, if proven successful, could complement existing therapeutic models and significantly increase response rates in cancer patients and/or expand the reach of immunotherapies to a wider range of cancer types.
