Li Jing, Shayan Gulidanna, Avery Lyndsay, Jie Hyun-Bae, Gildener-Leapman Neil, Schmitt Nicole, Lu Bin Feng, Kane Lawrence P, Ferris Robert L
School of Medicine, Tsinghua University , Beijing, China.
Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Graduate Program - Deptartment of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA, USA.
Oncoimmunology. 2016 Sep 22;5(10):e1200778. doi: 10.1080/2162402X.2016.1200778. eCollection 2016.
Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors highly expressed on tumor infiltrating T lymphocytes (TIL). PD-1 inhibits T cell activation and type-1 T cell responses, while Tim-3 is proposed to mark more extensively exhausted cells, although the mechanisms underlying Tim-3 function are not clear. Trials of anti-PD-1 therapy have identified a large subset of non-responder patients, likely due to expression of alternative checkpoint molecules like Tim-3. We investigated the phenotypic and functional characteristics of T cells with differential expression of PD-1 (high/low) and Tim-3 (positive/negative), using TIL directly isolated from head and neck squamous cell carcinomas (HNSCC). Unexpectedly, we found that expression of Tim-3 alone does not necessarily mark TIL as dysfunctional/exhausted. In Tim-3-TIL, PD-1 levels correlate with T cell dysfunction, with a PD-1 phenotype identifying recently activated and still functional cells, whereas PD-1Tim-3 T cells are actually exhausted. Nonetheless, PD-1 cells are still potently suppressed by PD-L1. PD-1 expression was associated with reduced phosphorylation of ribosomal protein S6 (pS6), whereas Tim-3 expression was associated with increased pS6. Using a novel mouse model for inducible Tim-3 expression, we confirmed that expression of Tim-3 does not necessarily render T cells refractory to further activation. These results suggest the existence of PD-1 and Tim-3 crosstalk in regulating antitumor T cell responses, with important implications for anti-PD-1 immunotherapy.
程序性死亡蛋白1（PD-1）和T细胞免疫球蛋白黏蛋白3蛋白（Tim-3）是在肿瘤浸润性T淋巴细胞（TIL）上高度表达的免疫检查点受体。PD-1抑制T细胞活化和1型T细胞反应，而Tim-3被认为标记了更广泛耗竭的细胞，尽管Tim-3功能的潜在机制尚不清楚。抗PD-1治疗试验已经确定了很大一部分无反应患者，这可能是由于Tim-3等替代检查点分子的表达。我们使用直接从头颈部鳞状细胞癌（HNSCC）中分离的TIL，研究了PD-1（高/低）和Tim-3（阳性/阴性）差异表达的T细胞的表型和功能特征。出乎意料的是，我们发现单独Tim-3的表达不一定将TIL标记为功能失调/耗竭。在Tim-3阴性的TIL中，PD-1水平与T细胞功能障碍相关，PD-1表型识别最近活化且仍有功能的细胞，而PD-1Tim-3双阳性T细胞实际上已耗竭。尽管如此，PD-1阳性细胞仍被PD-L1有效抑制。PD-1表达与核糖体蛋白S6（pS6）磷酸化减少有关，而Tim-3表达与pS6增加有关。使用一种新型的可诱导Tim-3表达的小鼠模型，我们证实Tim-3的表达不一定使T细胞对进一步活化产生抗性。这些结果表明在调节抗肿瘤T细胞反应中存在PD-1和Tim-3的相互作用，这对抗PD-1免疫疗法具有重要意义。
