A tumor-infiltrating IL23R-expressing CD4+ Treg population represents a safe and potent immunotherapeutic candidate in mice

Interleukin 23 receptor (IL23R) is a signaling protein normally implicated in gut T cell development, but which has also been correlated with poor cancer prognoses. Previous studies have found that interfering with this pathway results in improved cancer outcomes in mice. These studies found that blocking IL23R was more effective than neutralizing IL23, suggesting that an IL23R-expressing cell was responsible for the tumor-protective effects observed in targeting IL23R. Here, we show that Treg-specific targeting of IL23R provides potent tumor immunity that explains previous successes with anti-IL23R therapy in cancer. We show that there is indeed a tumor-infiltrating Treg subset, marked by IL23R expression, that is enriched for markers of potent suppressive activity. Moreover, we find that targeting their IL23R expression is correlated with Treg conversion and increased IFNγ expression on tumor-infiltrating CD8 T cells. Preliminary results suggest that this Treg conversion is associated with enhanced IL12 sensitivity as a result of targeting the IL23R chain. In keeping with the tumor-specific expression pattern of IL23R, we did not find these changes in systemic T cells in the tumor-bearing mice. Ultimately, these Treg-specific IL23R-deleted mice do not display overt autoimmune disease at even advanced ages, suggesting this approach could represent a safe avenue of cancer immunotherapeutic research.