LC3 and NLRC5 interaction inhibits NLRC5-mediated MHC class I antigen presentation pathway in endometrial cancer.

Guo Chen,Lei Zhan,Junhui Zhang,Suding Zhu,Bing Wei,Yijun Fan,Yu He,Yuchuan Shi,Jing Zhang,Zhenhai Tang,Yunxia Cao,Xiaojing Liu,Wenyan Wang

doi:10.1016/j.canlet.2021.12.031

Abstract

The major histocompatibility complex class I (MHC-I) transactivator, nucleotide binding oligomerization domain-like receptor family caspase recruitment domain containing 5 (NLRC5), serves as a target for immune evasion in many cancers, including endometrial cancer (EC). An inhibition of autophagy can contribute to immunotherapy by assisting the MHC-I-mediated antigen presentation in cancer. However, the underlying mechanism for autophagy-regulated MHC-I in EC remains unclear. In this study, we found that autophagy was upregulated in EC tissues when compared to that in normal endometrial tissues. MHC I and NLRC5 expressions were lower in EC endometrium than in normal endometrium. Autophagy inhibited the MHC-I genes expression in vitro. Furthermore, a negative correlation was found between NLRC5 and LC3 levels, and LC3 interacted with NLRC5 to inhibit NLRC5-mediated MHC-I antigen presentation pathway in vitro and in vivo. Thus, our findings demonstrated that an upregulation of LC3 in EC patients may contribute to tumor immune escape by restricting the NLRC5-mediated MHC-I antigen presentation pathway, signifying inhibiting LC3 and promoting NLRC5 may be a promising immunotherapy strategy in the management of EC.

Highlights

The major histocompatibility complex class I (MHC- I) transactivator, nucleotide binding oligomerization domain-like receptor family caspase recruitment domain containing 5 (NLRC5), serves as a target for immune evasion in many cancers, including endometrial cancer (EC)
An upregulation of LC3 in EC patients may contribute to tumor immune escape by restricting the NLRC5-mediated major histocompatibility complex class I (MHC-I) antigen presentation pathway, suggesting that inhibiting LC3 and promoting NLRC5 may be a promising immunotherapy strategy in the management of EC
We further confirmed the levels of HLA-A, LMP2, TAP1, β-2M were decreased in endometrium of EC patients as compared to those in normal endometrium by western blotting and quantitative reverse transcription PCR (qRT-PCR) (Fig. 1D)

Summary

Introduction

The major histocompatibility complex class I (MHC- I) transactivator, nucleotide binding oligomerization domain-like receptor family caspase recruitment domain containing 5 (NLRC5), serves as a target for immune evasion in many cancers, including endometrial cancer (EC). An inhibition of autophagy can contribute to immunotherapy by assisting the MHC-I-mediated antigen presentation in cancer. Our study aimed to investigate the effect of autophagy on NLRC5 and MHC-I-mediated antigen presentation, and to identify the potential mechanisms underlying this process in EC. Researchers have discovered a novel treatment, known as tumor immunotherapy, which trains the body’s immune system to kill the tumor cells but not the healthy cells [6]. Immunotherapy for EC has been widely investigated, and pre-clinical studies and clinical trials have revealed its promising potential [8, 9]. Some obstacles occur during tumor immunotherapy, and one of the most difficult problems is the immune escape of tumor cells [10]

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Discussion

Conclusion