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.

• 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
• Electronic ISSN: 2076-393X
• 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