Antibody-mediated blockade of the IL-23 receptor destabilizes intratumoral regulatory T cells and enhances immunotherapy

Regulatory T cells (Treg) can impede anti-tumor immunity and currently represent a major obstacle to effective cancer immunotherapy. Targeting tumor-infiltrating regulatory Treg while sparing systemic Treg represent optimal approaches to this problem. Here, we provide evidence that the interleukin 23 receptor (IL23R) expressed by tumor-infiltrating Treg promotes suppressive activity. Disruption of the IL23R results in increased responsiveness of destabilized Treg to the IL-12 cytokine, production of g-interferon (IFNg) and recruitment of CD8 T cells that inhibit tumor growth. Since the Treg destabilization pathway that is initiated by IL23R blockade is distinct and independent from the destabilization pathway coupled to Glucocorticoid-Induced TNFR-Related protein (GITR) activation, we examined the impact of coordinate induction of the two destabilization pathways on anti-tumor immune responses. Combined GITR and IL23R antibody treatment of mice inoculated with MC38 tumors resulted in robust and synergistic anti-tumor responses. These findings indicate that delineation of independent Treg destabilization pathways may allow improved approaches to the development of combination immunotherapy for cancers. 4 replicates of spleen and tumor-infiltrating Treg from WT (IL23RWT/WT FoxP3Cre) and 3 replicates of Treg-specific KO (IL23RFlox/Flox FoxP3Cre) (14 samples total). In all cases, comparisons are between Flox and WT samples within the same tissue type.