TIM-3 Expression Characterizes Regulatory T Cells in Tumor Tissues and Is Associated with Lung Cancer Progression

Abstract

BackgroundT cell immunoglobulin-3 (TIM-3) has been established as a negative regulatory molecule and plays a critical role in immune tolerance. TIM-3 is upregulated in exhausted CD8+ T cells in both chronic infection and tumor. However, the nature of TIM-3+CD4+ T cells in the tumor microenvironment is unclear. This study is to characterize TIM-3 expressing lymphocytes within human lung cancer tissues and establish clinical significance of TIM-3 expression in lung cancer progression.MethodologyA total of 51 human lung cancer tissue specimens were obtained from pathologically confirmed and newly diagnosed non-small cell lung cancer (NSCLC) patients. Leukocytes from tumor tissues, distal normal lung tissues, and peripheral blood mononuclear cells (PBMC) were analyzed for TIM-3 surface expression by flow cytometry. TIM-3 expression on tumor-infiltrating lymphocytes (TILs) was correlated with clinicopathological parameters.ConclusionsTIM-3 is highly upregulated on both CD4+ and CD8+ TILs from human lung cancer tissues but negligibly expressed on T cells from patients' peripheral blood. Frequencies of IFN-γ+ cells were reduced in TIM-3+CD8+ TILs compared to TIM-3−CD8+ TILs. However, the level of TIM-3 expression on CD8+ TILs failed to associate with any clinical pathological parameter. Interestingly, we found that approximately 70% of TIM-3+CD4+ TILs expressed FOXP3 and about 60% of FOXP3+ TILs were TIM-3+. Importantly, TIM-3 expression on CD4+ T cells correlated with poor clinicopathological parameters of NSCLC such as nodal metastasis and advanced cancer stages. Our study reveals a new role of TIM-3 as an important immune regulator in the tumor microenvironment via its predominant expression in regulatory T cells.

Tim-3: An Emerging Target in the Cancer Immunotherapy Landscape

“…In patients with NSCLC, approximately 60% of CD4 þ FoxP3 þ TILs express Tim-3. Interestingly, these Tim-3 þ Tregs are infrequent in the peripheral blood of patients with NSCLC, and the presence of Tim-3 þ Tregs correlates with the presence of nodal metastases and advanced cancer stage (11). Importantly, the presence of Tim-3 þ Tregs seems to be a common feature across multiple different cancers as Tim-3 þ Tregs have been reported in hepatocellular, ovarian, colon, and cervical carcinomas (20).…”

“…In patients with advanced melanoma, approximately 30% of NY-ESO-1-specific CD8 þ T cells express Tim-3 (10). In patients with non-small cell lung cancer (NSCLC), approximately one third of CD8 þ tumor-infiltrating lymphocytes (TIL) express Tim-3 (11). In patients with follicular B-cell non-Hodgkin lymphoma (FL; ref.…”

“…Coblockade of Tim-3 and PD-1 further restores IL-2 production in NY-ESO-1-specific CD8 þ T cells. In NSCLC, Tim-3 is uniquely expressed on the CD4 þ and CD8 þ T cells that infiltrate tumor (11). The CD8 þ Tim-3 þ TILs in NSCLC coexpress PD-1 and exhibit dysfunctional phenotype.…”

“…PD-1 is similarly upregulated on all effector T cells, and autoimmune-like toxicities also are observed in patients treated with anti-PD-1 antibodies (2,3). In this regard, targeting Tim-3 is advantageous as Tim-3 is not expressed on all T cells; rather, it is selectively expressed on T cells that have differentiated toward an IFN-g-producing phenotype (4), and in patients with cancer, Tim-3 seems to be expressed primarily in intratumoral T cells (11,12). Thus, Tim-3 blockade is less likely to interfere with the regulation of T-cell responses outside of tumor tissue than blockade of either CTLA-4 or PD-1.…”

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…It suggested that 2 coinhibitory receptors are correlated with dysfunction of T cells as well as tumor progression. [41][42][43] Collectively, targeting TIM-3 and PD-1 will potentially restore T cell function, which is worthy to be investigated in clinical practice. 44 Two clinical studies regarding dual targeted therapy on advanced malignancies are in development (NCT02817633 and NCT02608268; Table 1).…”