4.8 Article

Inhibition of PCSK9 enhances the antitumor effect of PD-1 inhibitor in colorectal cancer by promoting the infiltration of CD8+ T cells and the exclusion of Treg cells

期刊

FRONTIERS IN IMMUNOLOGY
卷 13, 期 -, 页码 -

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.947756

关键词

PD-1; CD8(+) T cells; regulatory T cells; tumor microenvironment; PCSK9

资金

  1. Science and Technology Supporting Project by Shanghai Municipal Science and Technology Committee
  2. Shanghai Sailing Program
  3. [19431903000]
  4. [21YF1401900]

向作者/读者索取更多资源

Immunotherapy, specifically immune checkpoint inhibitors (ICIs), has shown positive clinical outcomes for cancer patients. However, the effectiveness of ICIs in colorectal cancer (CRC) is still unsatisfactory. This study explores novel mechanisms of relapse during anti-PD-1 therapy in CRC models. The findings suggest that inhibiting PCSK9 can enhance the antitumor effect of anti-PD-1 therapy, indicating a promising approach to improve the efficacy of ICIs in CRC.
Immunotherapy especially immune checkpoint inhibitors (ICIs) has brought favorable clinical results for numerous cancer patients. However, the efficacy of ICIs in colorectal cancer (CRC) is still unsatisfactory due to the poor median progression-free survival and overall survival. Here, based on the CRC models, we tried to elucidate novel relapse mechanisms during anti-PD-1 therapy. We found that PD-1 blockade elicited a mild antitumor effect in these tumor models with both increased CD8(+) T cells and Treg cells. Gene mapping analysis indicated that proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor, transforming growth factor-beta (TGF-beta), and CD36 were unexpectedly upregulated during PD-1 blockade. To investigate the critical role of these proteins especially PCSK9 in tumor growth, anti-PCSK9 antibody in combination with anti-PD-1 antibody was employed to block PCSK9 and PD-1 simultaneously in CRC. Data showed that neutralizing PCSK9 during anti-PD-1 therapy elicited a synergetic antitumor effect with increased CD8(+) T-cell infiltration and inflammatory cytokine releases. Moreover, the proportion of Treg cells was significantly reduced by co-inhibiting PCSK9 and PD-1. Overall, inhibiting PCSK9 can further enhance the antitumor effect of anti-PD-1 therapy in CRC, indicating that targeting PCSK9 could be a promising approach to potentiate ICI efficacy.

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