Li Zhao, Liu Xiaobing, Guo Rongbin, Wang Pengfei
Department of Neurosurgery, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, china.
Tumour Biol. 2017 May;39(5):1010428317698352. doi: 10.1177/1010428317698352.
Cancer immunotherapy using cytotoxic T cells demonstrates dramatic survival benefits in lymphomas, but its efficacy in solid tumors is limited. Here, we investigated the possibility of using cytotoxic T cells to treat malignant Schwannoma, a rare but aggressive nerve sheath tumor, by examining the native T-cell immunity in the host. We found that compared to CD8 T cells from healthy controls or benign Schwannoma patients, the CD8 T cells from malignant Schwannoma patients were present at normal frequencies but were substantially enriched with PD-1TIM-3 and PD-1TIM-3 cells. Compared to the PD-1TIM-3 CD8 T cells, the PD-1TIM-3 and PD-1TIM-3 CD8 T cells presented significantly lower proliferation capacity, reduced interleukin 2 and interferon gamma expression, and/or dramatically decreased perforin and granzyme B secretion, indicating a whole-spectrum immunosuppression and reduced cytotoxicity. TIM-3 expression alone was associated with lower proliferation and less perforin and granzyme B secretion, whereas PD-1 expression alone was not associated with functional impairments, suggesting that TIM-3 expression was a better marker of exhausted CD8 T cells. The expression of galectin 9, a TIM-3 ligand, in CD4 Th cells was significantly elevated in malignant, but not benign, Schwannoma patients and were enriched in CD25 Treg cells. Both the PD-1TIM-3 and PD-1TIM-3 CD8 T cells responded to Treg-mediated and galectin 9-mediated suppression, whereas the PD-1TIM-3 CD8 T cells only responded to Treg-mediated suppression. In resected tumors, the malignant Schwannomas had more tumor-infiltrating CD4 and CD8 T cells than the benign Schwannomas, but a large fraction of these tumor-infiltrating CD4 and CD8 T cells expressed PD-1 and/or TIM-3, which indicated that their antitumor immunity was compromised. Together, our results suggested that PD-1 and TIM-3 blockade might be necessary in developing effective immunotherapeutic strategies in malignant Schwannoma, in which TIM-3 may play a more important role.
使用细胞毒性T细胞的癌症免疫疗法在淋巴瘤治疗中显示出显著的生存益处，但其在实体瘤中的疗效有限。在此，我们通过检测宿主中的天然T细胞免疫，研究了使用细胞毒性T细胞治疗恶性神经鞘瘤（一种罕见但侵袭性强的神经鞘肿瘤）的可能性。我们发现，与来自健康对照或良性神经鞘瘤患者的CD8 T细胞相比，恶性神经鞘瘤患者的CD8 T细胞频率正常，但PD-1⁺TIM-3⁺和PD-1⁺TIM-3⁻细胞显著富集。与PD-1⁻TIM-3⁻ CD8 T细胞相比，PD-1⁺TIM-3⁺和PD-1⁺TIM-3⁻ CD8 T细胞的增殖能力显著降低，白细胞介素2和干扰素γ表达减少，和/或穿孔素和颗粒酶B分泌显著减少，表明存在全谱免疫抑制和细胞毒性降低。单独的TIM-3表达与较低的增殖以及较少的穿孔素和颗粒酶B分泌相关，而单独的PD-1表达与功能受损无关，这表明TIM-3表达是耗竭性CD8 T细胞的更好标志物。在恶性而非良性神经鞘瘤患者中，TIM-3配体半乳糖凝集素9在CD4 Th细胞中的表达显著升高，并在CD25⁺ Treg细胞中富集。PD-1⁺TIM-3⁺和PD-1⁺TIM-3⁻ CD8 T细胞均对Treg介导的和半乳糖凝集素9介导的抑制有反应，而PD-1⁻TIM-3⁻ CD8 T细胞仅对Treg介导的抑制有反应。在切除的肿瘤中，恶性神经鞘瘤比良性神经鞘瘤有更多的肿瘤浸润性CD4和CD8 T细胞，但这些肿瘤浸润性CD4和CD8 T细胞中有很大一部分表达PD-1和/或TIM-3，这表明它们的抗肿瘤免疫受到损害。总之，我们的结果表明，在开发针对恶性神经鞘瘤的有效免疫治疗策略中，PD-1和TIM-3阻断可能是必要的，其中TIM-3可能起更重要的作用。
