Significance
Regulatory T cells rely on active processes to maintain a suppressive phenotype inside a tumor, leading to increased tumor burden and worse cancer outcomes. Here, we report a pathway to interfere with regulatory T cell (Treg) stability by disrupting the expression of the interleukin 23 receptor. This approach increases Treg responsiveness to interleukin 12, leading to increased production of gamma-interferon and more efficient antitumor immune responses. The combined engagement of independent pathways to destabilize Treg through the interleukin 23 receptor and the glucocorticoid-induced TNFR-related protein receptor has a synergistic impact on the Treg phenotype and promotes antitumor immune responses. These findings expand our understanding of regulatory T-cell biology and offer tools for cancer immunotherapy.
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.
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