Intermittent administration of tacrolimus enhances 
anti-tumor immunity in melanoma-bearing mice.

Abstract

One key reason for T cell exhaustion is continuous antigen exposure. Early exhausted T cells can reverse exhaustion and differentiate into fully functional memory T cells if removed from persisting antigen stimulation. Therefore, this study viewed T cell exhaustion as an over-activation status induced by chronic antigen stimuli. This study hypothesized that blocking TCR signal intermittently to terminate over-activation signal can defer the developmental process of T cell exhaustion. In this study, melanoma-bearing mice were treated with tacrolimus (FK506) every 5 days. The tumor size and tumor-infiltrating lymphocytes (TILs) were analyzed. We found that intermittent administration of tacrolimus significantly inhibited tumor growth, and this effect was mediated by CD8+T cells. Intermittent tacrolimus treatment facilitated the infiltration of CD8+TILs. RNA-seq and quantitative RT-PCR of sorted CD8+TILs showed the expression of Nr4a1 (an exhaustion-related transcription factor) and Ctla4 (a T cell inhibitory receptor) was remarkably downregulated. These results indicated that intermittently blocking TCR signal by tacrolimus can promote anti-tumor immunity and inhibit the tumor growth in melanoma-bearing mice, inhibiting the transcription of several exhaustion-related genes, such as Nr4a1 and Ctla4.

• Authors: Ting Chen, Qi Zhang, Nianhai Zhang, Bo Liu, Junying Chen, Fei Huang, Jianhua Lin, Ruilong Lan, Xianhe Xie, Zili Wang
• Journal: Carcinogenesis (Carcinogenesis) Vol. 43 Issue 4 Pg. 338-348 (05 19 2022) ISSN: 1460-2180 [Electronic] England
• PMID: 35136987 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• CTLA-4 Antigen
• Tacrolimus

Topics

• Animals
• CD8-Positive T-Lymphocytes
• CTLA-4 Antigen (metabolism)
• Lymphocytes, Tumor-Infiltrating
• Melanoma (drug therapy, metabolism)
• Mice
• Tacrolimus (metabolism, pharmacology)