Korean J Transplant.  2023 Nov;37(Suppl 1):S244. 10.4285/ATW2023.F-8380.

Proteomics analysis of tumor-infiltrated T cell reveals CD127+ and KLRG1+ memory CD8+ T cells control immunotherapy efficacy in hepatocellular carcinoma

• Wang S
• Xu N
• Wang J
• Wei Q
• Xu X

• KMID: 2551873
• DOI: http://doi.org/10.4285/ATW2023.F-8380

Abstract

Background
Low reactivity and short duration of tumor-infiltrated T cells limit hepatocellular carcinoma (HCC) immunotherapy efficacy. The proliferative ability of T cells maybe accounts for these deficiencies. This study firstly aimed to define the key factor regulating TILs proliferation in HCC microenvironment. By performing tissue-infiltrated T cell proteomics and fraction proteomics, we analyzed the differential proteins of T cells among HCC, liver fibrosis and hemangioma (as control) groups and the differential regulatory TFs of T cells between HCC and volunteer healthy (as control) groups.
Methods
Using cyTOF and flow cytometry technologies and constructing CD8+ T-specific BMI1 knockout mice, we verified BMI1 controls CD127+KLRG1+ memory cells differentiation which implicates better prognosis in HCC. Through performing RNA-seq and MeRIP-seq, we verified BMI1 regulating TCF1 expression independent on its classical function. Combined TSA IHC analysis, hydrodynamic mice HCC model and liver-specific nanoparticle packaged BMI1 shRNA, we demonstrated HCC BMI1 expression affects infiltrated T proliferation by affecting BMI1 expression.
Results
BMI1 inhibition promotes effector T cell differentiation, while BMI1 upregulation induces memory T differentiation. Moreover, destruction of BMI1 expression feedback between tumor cells and T cells promotes HCC progression and T cells dysfunction. Liver-specific BMI1 knockdown is helpful to attenuate T cells dysfunction and slow HCC progression.
Conclusions
Our group firstly explores the proteomics of HCC-infiltrated T cells and clarifies that BMI1 controls CD127⁺KLRG1⁺ memory CD8+ T cell differentiation is the cornerstone for immunotherapy efficacy in HCC.