Transcriptomic profiling of tumor-infiltrating CD4 + TIM-3 + T Cells reveals their suppressive, exhausted, and metastatic characteristics in colorectal cancer patients

Sasidharan Nair, V; Toor, SM; Taha, RZ; Ahmed, AA; Kurer, MA; Murshed, K; Soofi, ME; Ouararhni, K; Alajez, NM; Abu Nada, M; Elkord, E

Abstract

T cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint identified as one of the key players in regulating T-cell responses. Studies have shown that TIM-3 is upregulated in the tumor microenvironment (TME). However, the precise role of TIM-3 in colorectal cancer (CRC) TME is yet to be elucidated. We performed phenotypic and molecular characterization of TIM-3+ T cells in the TME and circulation of CRC patients by analyzing tumor tissues (TT, TILs), normal tissues (NT, NILs), and peripheral blood mononuclear cells (PBMC). TIM-3 was upregulated on both CD4+ and CD3+CD4− (CD8+) TILs. CD4+TIM-3+ TILs expressed higher levels of T regulatory cell (Tregs)-signature genes, including FoxP3 and Helios, compared with their TIM-3− counterparts. Transcriptomic and ingenuity pathway analyses showed that TIM-3 potentially activates inflammatory and tumor metastatic pathways. Moreover, NF-κB-mediated transcription factors were upregulated in CD4+TIM-3+ TILs, which could favor proliferation/invasion and induce inflammatory and T-cell exhaustion pathways. In addition, we found that CD4+TIM-3+ TILs potentially support tumor invasion and metastasis, compared with conventional CD4+CD25+ Tregs in the CRC TME. However, functional studies are warranted to support these findings. In conclusion, this study discloses some of the functional pathways of TIM-3+ TILs, which could improve their targeting in more specific therapeutic approaches in CRC patients.

Citation

Sasidharan Nair, V., Toor, S., Taha, R., Ahmed, A., Kurer, M., Murshed, K., …Elkord, E. (2020). Transcriptomic profiling of tumor-infiltrating CD4 + TIM-3 + T Cells reveals their suppressive, exhausted, and metastatic characteristics in colorectal cancer patients. Vaccines, 8(1), e71. https://doi.org/10.3390/vaccines8010071

• Journal Article Type: Article
• Acceptance Date: Feb 4, 2020
• Publication Date: Feb 6, 2020
• Deposit Date: Feb 10, 2020
• Publicly Available Date: Feb 10, 2020
• Journal: Vaccines
• Publisher: MDPI
• Volume: 8
• Issue: 1
• Pages: e71
• DOI: https://doi.org/10.3390/vaccines8010071
• Keywords: colorectal cancer, tumor microenvironment, T cell immunoglobulin mucin-3, exhausted T cells, metastasis
• Publisher URL: https://doi.org/10.3390/vaccines8010071
• Related Public URLs: https://www.mdpi.com/journal/vaccines
• Additional Information: Additional Information : ** From MDPI via Jisc Publications Router ** Licence for this article: https://creativecommons.org/licenses/by/4.0/ **Journal IDs: eissn 2076-393X **History: published 06-02-2020; accepted 04-02-2020; Funders : Qatar Foundation; Grant Number: VR04