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

Varun Sasidharan Nair,Rowaida Z Taha,Khaled Murshed,Mohamed Abu Nada,Ayman A Ahmed,Mohamed A Kurer,Madiha E Soofi,Eyad Elkord,Salman M Toor,Nehad M Alajez,Khalid Ouararhni

doi:10.3390/vaccines8010071

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.

Highlights

Colorectal cancer (CRC) is the fourth most common cancer among both men and women, with nearly 1.09 million new cases and 0.55 million deaths each year worldwide [1]
T cell immunoglobulin mucin-3 (TIM-3) has been identified as a potential prognostic biomarker in various solid malignancies, including colorectal cancer (CRC), in which higher TIM-3 expression has been shown to be associated with decreased overall survival [12]
We found that programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) are mainly co-expressed on CD4+ T cells but there are no significant differences in their co-expression within CD4+ TIM-3+/− cells in colorectal tumor microenvironment (TME) (Figure 2G,I)

Summary

Introduction

Colorectal cancer (CRC) is the fourth most common cancer among both men and women, with nearly 1.09 million new cases and 0.55 million deaths each year worldwide [1]. Vaccines 2020, 8, 71 checkpoints (IC) in suppression of anti-tumor immune responses to various malignancies provided new targets for immunotherapy. Despite the clinical efficacy of current available immunotherapies in cancer patients, a large proportion of CRC patients fail to respond mainly due to immune-cell mediated resistance [2]. Later studies revealed that TIM-3 can be expressed on other immune subsets, including T regulatory cells (Tregs) [5]. Accumulating evidence suggests that expression of TIM-3 on tumor-infiltrating lymphocytes (TILs) has an indispensable role in tumor biology [8,9]. TIM-3 plays an important role in tumorigenesis and progression of prostate cancer and has a potential prognostic value as a biomarker [10]. TIM-3 serves as a potential mediator for tumor progression in CRC [9]

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Conclusion