The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Wang, X., Fang, Y., Liang, W. et al. Cancer Cell. 42 (10): 1729-1746.e8 (2024).
doi: 10.1016/j.ccell.2024.08.019.
Summary of the findings
Summary of the findingsImmune checkpoint blockade (ICB) therapy is one of the most promising strategies for treatment of cancer. However, 85% of patients with CRC are microsatellite stable (MSS) and are ineligible to ICB therapy due to poor responsiveness. Here, Wang et al. report that CRC-promoting gut pathogen, Fusobacterium nucleatum (Fn), paradoxically sensitizes MSS CRC to anti-programmed death-1 (PD-1) therapy. Fecal microbiota transplantation from MSS CRC patients with Fn-high abundance to germ-free MSS CRC mice conferred sensitivity to anti-PD-1 treatment compared to those receiving transplants from Fn-low counterparts. Consistent with this, Fn gavage in humanized, germ-free mice similarly boosted anti-PD1 efficacy against MSS CRC tumors.
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This study further identified that Fn mediates anti-PD-1 promoting effect through its secreted metabolite butyric acid. Butyric acid acts as histone deacetylase (HDAC) inhibitor, suppressing HDAC3/8 activities in intratumoral CD8+ T cells, leading to the acetylation of histone H3 on lysine 27 at Tbx21 promoter region and subsequent over-expression of TBX21 protein. TBX21 in turn represses PD-1 expression, alleviating CD8+ T cell exhaustion and promoting the production of tumor killing cytokines. In patients with MSS CRC, high intratumoral Fn predicts a favorable response to anti-PD-1 therapy, indicating Fn as a potential biomarker for immunotherapy response in MSS CRC.
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Future impact
MSS CRC is resistant to anti-PD-1 therapy. The findings by Wang et al. have translational relevance for novel strategy to boost anti-PD1 therapy in MSS CRC. By showing that high Fn abundance potentiates anti-PD-1 efficacy, this work implies that Fn abundance may be a potential biomarker for predicting responses to anti-PD-1 therapy in MSS CRC, which could help stratify patients who are likely to respond. Additionally, the identification of butyric acid as a key metabolite that activates intratumoral CD8+ T cells infers that increasing colonic butyric acid production could be a strategy to improve response to anti-PD-1 therapy in MSS CRC.
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