Blockade of TIM3 relieves immunosuppression through reducing regulatory T cells in head and neck cancer

Abstract

BackgroundT-cell immunoglobulin mucin 3 (TIM3) is a negative immune checkpoint and plays a crucial part in tumor-induced immune suppression. However, the mechanism of TIM3 in regulating immunosuppression in head and neck squamous cell carcinoma (HNSCC) was still not quite clear.MethodsWe carried out the immunohistochemistry staining of HNSCC tissue microarrays. Through quantification of the histoscore, we performed the correlation analysis among the TIM3, Galectin-9, Foxp3, CD68 and CD163. The effects of TIM3 on regulatory T cells (Tregs) and macrophages were detected by utilizing the Tgfbr1/Pten 2cKO HNSCC mouse model. Flow cytometry were used to analysis the percent of Tregs, macrophages and IFN-γ.ResultsWe demonstrated the close association among TIM3/Galectin-9 pathway, regulatory T cell marker (Foxp3) and macrophage marker (CD68, CD163) in human HNSCC. In the transgenic HNSCC mouse model, blockade of TIM3 by the anti-TIM3 monoclonal antibody induced a reduction of CD4+CD25+Foxp3+ Tregs. Meanwhile, the population of TIM3+ Tregs was also decreased. However, the population of CD206+ macrophages was not significantly declined. The increased IFN-γ production on CD8+ T cells in anti-TIM3 treatment mice showed that the antitumor immune response was enhanced through suppression of these negative immune factors.ConclusionsThe present study demonstrated that TIM3 was associated with the immunosuppression in HNSCC. And targeting TIM3 can enhance anti-tumor immune response by decreasing Tregs in HNSCC.

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

“…Accumulating evidences from in vivo studies have shown that TIM-3 blockade enhances anti-tumor immunity and suppresses tumor growth [11,31]. Therefore, TIM-3 could be considered as a potential candidate for IC inhibition due to the remarkable success of other IC inhibitors in treating various cancers.…”

Activities of stromal and immune cells in HPV-related cancers

“…A decrease in tumor growth and in Treg and CTLA-4 levels was observed following TIM-3 blockade, while M2 macrophage markers were not altered. Also, TIM-3 blockade caused a significant increase in IFN-γ synthesis, which highlights the importance of the use of this immune checkpoint protein in possible future immunotherapeutic approaches [ 73 ].…”

CD8+ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway

“…13 MDSCs, which are powerful cellular immunity suppressor, could badly inhibit the antitumour immune response mediated by the effector T cells and lead to tumour cells immunological surveillance escape. 28,29 Here, we found that Gal-9 was also highly expressed in MDSCs were much lower than that in real infectious diseases. These suggested that cellular immunity was insufficient for malignant clonal cells due to cellular immunity tolerance, both in low-risk and highrisk MDS groups.…”