Immune-checkpoint therapy resistance by tumor-intrinsic evolution in hepatocellular carcinoma
Refereed conference paper presented and published in conference proceedings

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AbstractImmune-checkpoint blockade (ICB) therapies have revolutionized the treatment paradigm for cancer. Although subsets of people exhibit durable responses, ICB resistance has increasingly been observed, especially in ‘cold’ cancers like hepatocellular carcinoma (HCC). To dissert the ICB resistance mechanisms, we first recapitulated the clinical outcome of ICB resistance via repeated cycles of in vivo selection in orthotopic-grafted murine models of HCC. As a result, anti-PD-L1 therapy failed to reduce tumor growth, which was accompanied with lower proportions of CD8+T cells and T helper 1 cells but higher exhausted T cells and myeloid-derived suppressor cells in the TME. Interestingly, single-cell RNA-sequencing (scRNA-seq) from anti-PD-L1-treated tumor cells uncovered significant enrichment of genes involved in lipid metabolism in PD-L1-resistant tumor cells, which could be verified using bulk RNA-seq of these cells lines. The results were further confirmed by RT-qPCR, Western blot and immunohistochemistry staining in tumor tissues. Our findings suggest that hepatoma-intrinsic lipid metabolic pathway may confer ICB resistance through reprogramming immunosuppressive TME in HCC.
All Author(s) ListZhewen XIONG, Jingying ZHOU, Jianquan CAO, Joaquim S. L. VONG, Xuezhen ZENG, Yu FENG, Alfred Sze-Lok CHENG
Name of ConferenceThe 79th Annual Meeting of the Japanese Cancer Association
Start Date of Conference01/10/2020
End Date of Conference03/10/2020
Place of ConferenceOnline
Country/Region of ConferenceHong Kong
LanguagesEnglish-United States
KeywordsImmunotherapy resistance, scRNA-seq, tumor evolution, lipid metabolism, immunosuppression

Last updated on 2021-06-12 at 11:12