TIM3-blockade synergizes with IL2 in alleviating intra-tumoral CD8+T cell exhaustion
Xuhao Zhang, Yu Gao, Huiping Liao, Wenyan Wang, Zaili Yang, Weian Cao, Ge Li, Jing Wen, Gencheng Han, Yang‐Xin Fu
Abstract
TIM3, a T-cell inhibitory receptor, is expressed on exhausted T cells in the TME. Progressive loss of IL2-secretion is an early sign of diminished effector function in TILs, which raises the possibility of IL2 loss driving exhaustion of TILs. We show that endogenous IL-2 is required for the antitumor effect of anti-TIM3. Selective delivery of IL-2 to TIM3high TILs via an engineered anti-TIM3-Pro-IL2 fusion enhances anti-TIM3 efficacy, while reducing IL2 toxicity. IL2 activity is inhibited at the acidic pH of the TME, thus an IL2 mutein (IL2V2) with sustained activity at low pH is integrated into the construct. Mechanistically, TIM3-ProIL2V2 not only reactivates TIM3+ TILs but also facilitates the activation and expansion of TIM3- TILs, which in turn provide a sustained source of effector T cells. TIM3-ProIL2V2 is efficient in multiple tumor models, including tumors in humanized mice. TIM3-ProIL2V2 has the potential to overcome anti-PD-1/L1 resistance in cold cancers. Blockade of alternative T cell checkpoint molecules, such as Tim3, is a promising alternative to inhibition of PD-1-PD-L1 interaction in cancers. Here authors show that anti-Tim3 therapy is working only in the presence of Il-2 co-stimulation, and the 2 necessary signals can be provided in the form of an anti-Tim3-Pro-Il2 construct, harboring modifications to the cytokine to resist the acidic tumour microenvironment.