Tim-3 is a promising target for antitumor immunotherapy. A number of clinical trials are evaluating the efficacy of anti-Tim-3 therapies as a single agent or combinations in solid tumors and haematologic malignancies. However, there remains a considerable lack of data on Tim-3 signalling, especially the genetic characteristics and immune microenvironment, in diffuse large B cell lymphoma (DLBCL). Herein, we identified three genetic mutations in galectin-9, a major ligand of Tim-3, in six patients with DLBCL (6/188, 3.2%) that were not detected in the COSMIC database. The Oncomine database showed that the mRNA levels of Tim-3 were higher in DLBCL cells than those in normal B cells. Multiplexed immunofluorescence revealed that patients with Tim-3-expressing tumor-infiltrating lymphocytes (Tim-3⁺ TILs) exhibited poor outcomes than those with Tim-3^- TILs (). The median survival times of these patients were 65.0 (95% confidence interval (CI): 71.2–88.6) and 79.9 months (95% CI: 54.4–75.6), respectively. Furthermore, we defined a novel subtype of exhausted T cells, named as exhausted Tim-3⁺ CD8⁺ T cells, and found that patients with exhausted Tim-3⁺ CD8⁺ T cells (median survival, 62.8 months, 95% CI: 50.0–75.6) exhibited shorter survival than those with nonexhausted Tim-3^- CD8⁺ T cells (median survival, 82.5 months, 95% CI: 72.0–92.9; ). Overall, these findings provide the genetic status of the Tim-3 ligand in DLBCL. Patients with Tim-3⁺ TILs and exhausted Tim-3⁺ CD8⁺ T cells exhibited inferior survival, thus highlighting the possibility of potential therapeutic applications of the inhibition of Tim-3 alone or in combination with other immune checkpoints for treatment of patients with DLBCL.

中文翻译：

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Tim-3 配体和耗尽的 Tim-3+ CD8+ T 细胞的遗传突变和弥漫性大 B 细胞淋巴瘤的存活

Tim-3 是抗肿瘤免疫治疗的一个有前景的靶点。许多临床试验正在评估抗 Tim-3 疗法作为单一药物或组合在实体瘤和血液系统恶性肿瘤中的疗效。然而，在弥漫性大 B 细胞淋巴瘤 (DLBCL) 中，Tim-3 信号传导的数据仍然相当缺乏，尤其是遗传特征和免疫微环境。在此，我们在 COSMIC 数据库中未检测到的 6 名 DLBCL 患者（6/188，3.2%）中发现了 galectin-9（Tim-3 的主要配体）中的三个基因突变。Oncomine 数据库显示 DLBCL 细胞中 Tim-3 的 mRNA 水平高于正常 B 细胞中的水平。多重免疫荧光显示，表达 Tim-3 的肿瘤浸润淋巴细胞（Tim-3 ⁺TILs) 的结果比 Tim-3 ^- TILs (）。这些患者的中位生存时间分别为 65.0（95% CI：71.2-88.6）和 79.9 个月（95% CI：54.4-75.6）。此外，我们定义了一种新的耗竭 T 细胞亚型，称为耗竭 Tim-3 ⁺ CD8 ⁺ T 细胞，并发现患有耗竭 Tim-3 ⁺ CD8 ⁺ T 细胞的患者（中位生存期，62.8 个月，95% CI：50.0 –75.6) 的存活率比未耗尽 Tim-3 ^- CD8 ⁺ T 细胞的存活率短（中位存活率，82.5 个月，95% CI：72.0–92.9；）。总体而言，这些发现提供了 DLBCL 中 Tim-3 配体的遗传状态。Tim-3 ⁺ TILs 和耗尽的 Tim-3 ⁺ CD8 ⁺ T 细胞的患者表现出较差的存活率，从而突出了单独抑制 Tim-3 或与其他免疫检查点联合治疗 DLBCL 患者的潜在治疗应用的可能性.