Sakuishi Kaori, Ngiow Shin Foong, Sullivan Jenna M, Teng Michele W L, Kuchroo Vijay K, Smyth Mark J, Anderson Ana C
Center of Neurologic Diseases; Department of Neurology; Brigham and Women's Hospital; Harvard Medical School; Boston, MA USA.
Oncoimmunology. 2013 Apr 1;2(4):e23849. doi: 10.4161/onci.23849.
T-cell immunoglobulin mucin 3 (TIM3) is an inhibitory molecule that has emerged as a key regulator of dysfunctional or exhausted CD8 T cells arising in chronic diseases such as cancer. In addition to exhausted CD8 T cells, highly suppressive regulatory T cells (Tregs) represent a significant barrier against the induction of antitumor immunity. We have found that the majority of intratumoral FOXP3 Tregs express TIM3. TIM3 Tregs co-express PD-1, are highly suppressive and comprise a specialized subset of tissue Tregs that are rarely observed in the peripheral tissues or blood of tumor-bearing mice. The co-blockade of the TIM3 and PD-1 signaling pathways in vivo results in the downregulation of molecules associated with TIM3 Treg suppressor functions. This suggests that the potent clinical efficacy of co-blocking TIM3 and PD-1 signal transduction cascades likely stems from the reversal of T-cell exhaustion combined with the inhibition of regulatory T-cell function in tumor tissues. Interestingly, we find that TIM3 Tregs accumulate in the tumor tissue prior to the appearance of exhausted CD8 T cells, and that the depletion of Tregs at this stage interferes with the development of the exhausted phenotype by CD8 T cells. Collectively, our data indicate that TIM3 marks highly suppressive tissue-resident Tregs that play an important role in shaping the antitumor immune response in situ, increasing the value of TIM3-targeting therapeutic strategies against cancer.
T细胞免疫球蛋白黏蛋白3（TIM3）是一种抑制性分子，已成为慢性疾病（如癌症）中功能失调或耗竭的CD8 T细胞的关键调节因子。除了耗竭的CD8 T细胞外，高抑制性调节性T细胞（Tregs）是诱导抗肿瘤免疫的重要障碍。我们发现肿瘤内大多数FOXP3 Tregs表达TIM3。TIM3 Tregs共表达PD-1，具有高度抑制性，构成组织Tregs的一个特殊亚群，在荷瘤小鼠的外周组织或血液中很少观察到。体内TIM3和PD-1信号通路的联合阻断导致与TIM3 Treg抑制功能相关分子的下调。这表明联合阻断TIM3和PD-1信号转导级联的强大临床疗效可能源于T细胞耗竭的逆转以及肿瘤组织中调节性T细胞功能的抑制。有趣的是，我们发现TIM3 Tregs在耗竭的CD8 T细胞出现之前就积聚在肿瘤组织中，并且在此阶段Tregs的耗竭会干扰CD8 T细胞耗竭表型的发展。总体而言，我们的数据表明TIM3标记了高度抑制性的组织驻留Tregs，它们在原位塑造抗肿瘤免疫反应中起重要作用，增加了针对癌症的TIM3靶向治疗策略的价值。
