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<p>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 TIM3<sup>high</sup> 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<sup>+</sup> TILs but also facilitates the activation and expansion of TIM3<sup>-</sup> 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.</p>

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TIM3-blockade synergizes with IL2 in alleviating intra-tumoral CD8+T cell exhaustion

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月3日

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  • Xuhao Zhang,
  • Yu Gao,
  • Huiping Liao,
  • Wenyan Wang,
  • Zaili Yang,
  • Weian Cao,
  • Ge Li,
  • Jing Wen,
  • Gencheng Han,
  • Yang-Xin Fu

摘要

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.