255O - Genetic mutations of Tim-3 ligand, and exhausted Tim-3+CD8+ T cells and survival in diffuse large B cell lymphoma

Background

Tim-3 is emerging as a promising target for antitumor immunotherapy. A number of clinical trials are ongoing to evaluate anti-Tim-3 therapies as a single agent or combinations in solid tumors and hematologic malignancies. However, there remains a considerable lack of data related to the information of Tim-3 signaling in diffuse large B-cell lymphoma (DLBCL), especially the genetic characteristics and immune microenvironment.

Methods

Here, next-generation sequencing was utilized to identify DLBCLs harboring genetic mutations of Tim-3 ligand, and multiple immunofluorescence staining and quantitative pathological analysis techniques were applied to determine the immune microenvironment.

Results

Three genetic mutations of galectin-9, which is a major ligand of Tim-3, were identified in six DLBCL patients (6/188, 3.2%). And these mutations had never been reported in DLBCL according to the COSMIC database. We further found that the Tim-3 mRNA level was significantly higher in DLBCL compared to that of normal B cells through the Oncomine database. Using multiplexed immunofluorescence staining, we found that patients with Tim-3 expression on tumor-infiltrating lymphocytes (Tim-3⁺ TILs) experienced significantly poorer outcomes than those with Tim-3^- TILs (p = 0.041), and the median survival times were 65.0 months (95% 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 also found that patients with exhausted Tim-3⁺CD8⁺ T cells (median survival, 62.8 months, 95% CI: 50.0–75.6) had a significantly shorter survival than those with non-exhausted Tim-3^-CD8⁺ T cells (median survival, 82.5 months, 95% CI: 72.0–92.9) (p = 0.034).

Conclusions

Overall, our findings provid an important addition to the genetic information of Tim-3 ligand in DLBCL. And we uncovered that patients with Tim-3⁺ TILs and exhausted Tim-3⁺ CD8⁺ T cells exhibited inferior survival, supporting potential strategies to block Tim-3 alone or in combination with other immune checkpoints as treatment options for DLBCL patients.

Clinical trial identification

Editorial acknowledgement

The authors thank the Marvel Medical Laboratory, Tianjin Marvelbio Technology Co.,Ltd (Tianjin, China) for the support of next-generation sequencing.

Funding

This study was supported by the Natural Science Foundation of Tianjin (19JCYBJC26500, 18JCZDJC45100), the National Natural Science Foundation of China (81770213, 81670184), the National Key New Drug Creation Special Programs (2017ZX09304-021, 2018ZX09201015), the Clinical Oncology Research Fund of CSCO (Y-XD2019-162), the Projects of Tianjin Municipal Health Bureau (15KG145), the National Human Genetic Resources Sharing Service Platform (2005DKA21300)/Cancer Biobank of Tianjin Medical University Cancer Institute and Hospital.

Disclosure

All authors have declared no conflicts of interest.