Document Type
Article
Publication Date
6-20-2024
Original Citation
Cai X,
Yin G,
Chen S,
Tacke F,
Guillot A,
Liu H.
CDK4/6 inhibition enhances T-cell immunotherapy on hepatocellular carcinoma cells by rejuvenating immunogenicity. Cancer Cell Int. 2024;24(1):215.
Keywords
JMG
JAX Source
Cancer Cell Int. 2024;24(1):215.
ISSN
1475-2867
PMID
38902716
DOI
https://doi.org/10.1186/s12935-024-03351-z
Grant
Open Access funding enabled and organized by Projekt DEAL. This work was funded by National Nature Science Foundation of China (82300730), Changzhou (China) Health Commission (CZQM2022007 and QN202121), Changzhou (China) Science and Technology Bureau (CJ20220142), Changzhou Medical Center of Nanjing Medical University (CZKYCMCB202221) and German Research Foundation (DFG Ta434/8 − 1, SFB/TRR 296 and CRC1382, Project-ID 403224013). Xiurong Cai, Guo Yin and Hanyang Liu were funded by China Scholarship Council.
Abstract
Hepatocellular carcinoma (HCC) poses a significant clinical challenge, necessitating the integration of immunotherapeutic approaches. Palbociclib, a selective CDK4/6 inhibitor, has demonstrated promising efficacy in preclinical HCC models and is being evaluated as a novel therapeutic option in clinical trials. Additionally, CDK4/6 inhibition induces cellular senescence, potentially influencing the tumor microenvironment and immunogenicity of cancer cells. In this study, we conducted comprehensive bioinformatic analyses using diverse HCC transcriptome datasets, including bulk and single-cell RNA-sequencing data from public databases. We also utilized human and mouse HCC cells to investigate functional aspects. Primary T cells isolated from mouse blood were employed to assess T cell immunity against HCC cells. Results revealed that CD8+ T-cell infiltration correlates with improved outcomes in HCC patients with suppressed CDK4/6 expression. Moreover, CDK4/6 expression was associated with alterations in the immune landscape and immune checkpoint expression within the liver tumor microenvironment. Furthermore, we found that treatment with Palbociclib and Doxorubicin induces cellular senescence and a senescence-associated secretory phenotype in HCC cells. Notably, pretreatment with Palbociclib augmented T cell-mediated cytotoxicity against HCC cells, despite upregulation of PD-L1, surpassing the effects of Doxorubicin pretreatment. In conclusion, our study elucidates a novel mechanism by which CDK4/6 inhibition enhances T-cell-associated cancer elimination and proposes a potential therapeutic strategy to enhance T-cell immunotherapy on HCC.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.