Cytotoxic T-Lymphocyte Antigen-4 in Colorectal Cancer: Another Therapeutic Side of Capecitabine.

Afshin Derakhshani,Pankaj Kumar Singh,Behzad Baradaran,Mahdi Abdoli Shadbad,Darya Javadrashid,Vahid Jafarlou,Farnaz Rasibonab,Antonio Giovanni Solimando,Souzan Najafi,Nicola Silvestris,Shahryar Hashemzadeh,Zahra Asadzadeh,Oronzo Brunetti,Hossein Safarpour,Vito Racanelli

doi:10.3390/cancers13102414

Abstract

Simple SummaryColorectal cancer (CRC) begins when normal cells turn out of balance, and a tumor is formed in the lining of the colon or rectum. Cytotoxic T-lymphocyte protein 4 (CTLA-4) is a potent molecule that could inhibit T cell activation. Here, we analyzed this molecule in the tissue samples and cell lines of colorectal cancer to reveal the mechanism of this inhibitory molecule in CRC. Our result showed an increasing trend of CTLA-4 in tissues and cell lines. Finally, capecitabine as an approved drug in CRC could suppress this inhibitory molecule. It can be concluded that the inhibition of this inhibitory molecule can re-active the immune cells, especially T cells, in CRC patients, which boosts the immune cells against the tumor. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory immune checkpoint that can be expressed in tumor-infiltrating lymphocytes and colorectal cancer (CRC) cells. This immune checkpoint can attenuate anti-tumoral immune responses and facilitate tumor growth and metastasis. Although capecitabine is an effective chemotherapeutic agent for treating CRC, its effect on the tumoral CTLA-4 expression remains unclear. In the current research, we applied the GSE110224 and GSE25070 datasets to characterize CTLA-4 expression in CRC patients. Then, we analyzed CTLA-4 expression in CRC samples, HT-29, HCT-166, and SW480 cell lines using real-time PCR. Our bioinformatic results have highlighted the overexpression of CTLA-4 in the CRC tissues compared to the adjacent non-tumoral tissues. Our in vitro studies have indicated that SW480 cells can substantially overexpress CTLA-4 compared to HT-29 and HCT 116 cells. In addition, capecitabine can remarkably downregulate the expression of CTLA-4 in SW480 cells. Collectively, capecitabine can inhibit the expression of CTLA-4 in CRC cells and might bridge the immunotherapy approaches with chemotherapy.

Highlights

colorectal cancer (CRC) is responsible for the third cause of cancer-related death among men and the second cause of cancer-related death among women [1]
Based on GSE110224 and GSE25070 datasets, we have found that Cytotoxic T lymphocyte antigen-4 (CTLA-4) expression is substantially upregulated in CRC tissues compared to adjacent non-tumor samples
The expression of CTLA-4 has been remarkably different among primary CRC, non-tumoral samples, recurrent tumors, and metastatic tumors

Summary

Introduction

CRC is responsible for the third cause of cancer-related death among men and the second cause of cancer-related death among women [1]. 50 percent of newly diagnosed CRC patients develop metastasis, which is associated with an inferior prognosis [2]. Inhibitory immune checkpoints can inhibit the development of anti-tumoral immune responses and pave the way for tumor proliferation and metastasis. Consistent with this, a recent meta-analysis has indicated that the gene expression of CTLA-4 can be associated with the inferior prognosis of affected patients (hazard ratio (HR): 1.50, 95% CI: 1.20–1.86) [4]. Targeting this pro-tumoral axis might be a promising strategy to improve the prognosis of CRC patients

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