The efficacy of HCC (hepatocellular carcinoma) immunotherapy is hindered by the limited reactivity and short duration of tumor-infiltrating T cells. These deficiencies may be ascribed to the proliferative ability of T cells. The primary objective of this study was to identify the key factor regulating tumor-infiltrating lymphocytes (TIL) proliferation within the HCC microenvironment. Through the utilization of tissue-infiltrated T cell proteomics and fraction proteomics, we analyzed the differential proteins in T cells among HCC, liver fibrosis, and hemangioma (serving as controls) groups. Additionally, we examined the differential regulatory TFs of T cells between the HCC and VH (volunteer healthy, as a control) groups. Using cyTOF and flow cytometry technologies, as well as generating CD8+ T-specific BMI1 knockout mice, we confirmed that BMI1 controls CD127+KLRG1+ memory cell differentiation. Through RNA-seq and MeRIP-seq, we verified that BMI1 regulates TCF1 expression independently of its classical function. Furthermore, by conducting Tyramide signal amplification (TSA) IHC analysis, employing a hydrodynamic mouse HCC model, and utilizing liver-specific nanoparticle targeting therapy, we demonstrated that BMI1 in HCC influences the proliferation of infiltrating CD8+T. BMI1 inhibition promotes effector T cell differentiation while suppressing memory T cell differentiation. Moreover, liver-specific BMI1 knockdown proves beneficial in ameliorating T cell dysfunction and decelerating HCC progression. Our research group has pioneered the exploration of the proteomics of HCC-infiltrated T cells, shedding light on the pivotal role of BMI1 in controlling CD127+KLRG1+ memory CD8+ T cell differentiation, which serves as the cornerstone for achieving immunotherapy efficacy in HCC.
Keywords: Esterase-responsive polymer (ERP); Hepatocellular carcinoma (HCC); N6-methyadeosine (m6A) modifications; TCF1; Tumor-infiltrated T cells (TILs).
Copyright © 2023 Elsevier B.V. All rights reserved.