Neutrophil profiling illuminates anti-tumor antigen-presenting potency![]()
Yingcheng Wu, et al.Neutrophils have been studied in inflammation and other diseases for a long time, but in recent years, research on neutrophils in the field of tumors has gradually become a hot topic. It is entirely unclear whether neutrophils play an immunosuppressive or immune-promoting role in the tumor microenvironment. In this study, the authors enriched 10 distinct neutrophil states including inflammation, angiogenesis, and antigen presentation from a large number of clinical samples of patients with different tumors. HLA-DR+CD74+Neu and VEGFA+SPP1+Neu were the two subsets with the highest proportion in tumors. Among them, HLA-DR+Neu was positively correlated with the prognosis of patients, indicating that it was an important anti-tumor neutrophil subset. Using single-cell sequencing data for the enrichment of metabolism-related pathways, it was found that amino acid metabolism was significantly up-regulated in the HLA-DR+ Neu subset, suggesting that amino acid metabolism initiated the HLA-DR program. In order to further clarify which amino acids play an important role as intermediate products, the authors enriched Neu from PBMC and activated it by LPS, and treated it with 20 amino acids. Leucine could significantly up-regulate the proportion of HLA-DR+Neu subsets by FACS, and clarified the important role of leucine in the initiation of HLA-DR-Neu. By ATACseq and CUT Tag technology, leucine could significantly enhance the H3K27ac modification of HLA-DRA and HLA-DQB1 in Neu, and promote the transcription of HLA-DRA and HLA-DQB1. Antigen-presenting effect as one of Neu functions, HLA-DR+ neutrophils are associated with an active TME and can broadly trigger T cell activation, (neo)antigen reactivity and cytotoxicity, raising the possibility that these cells could be delivered to fuel T cell responses. Altogether, these in vivo and human-sample-derived data highlighted the synergy of antigen-presenting neutrophils in immunotherapy and suggested therapeutic opportunities such as adoptive delivery. DOI: 10.1016/j.cell.2024.02.005
Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancerDingjiacheng Jia, et al.
The intestinal microbiota was closely related to the efficacy of immunotherapy, which was a hot topic of current research, but still many microbiota influence immunotherapy were not identified. In this study, Lactobacillus johnsonii was discovered by sequencing in the feces of mice bearing tumor with good and poor responses to immunotherapy. The effect of Lactobacillus johnsonii on enhancing anti-PD1 treatment was confirmed by experiments on mice model with CRC. To further explore the specific mechanism, the authors compared anti-PD1 with anti-PD1 combined with Lactobacillus johnsonii group to screen IPA intermediate metabolites by IP-MS technology. In order to further clarify the anti-tumor effect of IPA-mediated Lactobacillus johnsonii in promoting anti-PD1 therapy, the authors used IPA in combination with anti-PD1 and Lactobacillus johnsonii to treat tumor-bearing mice, and clarified the important role of IPA. The transfer assay further confirmed that IPA exerted anti-tumor effects by affecting CD8+ T cells.To explore the specific mechanism, the authors enriched CD8+ T from the anti-PD1 and anti-PD1+IPA groups for scRNAseq, and found that the Tpex subset was significantly increased after IPA combined with anti-PD1 treatment, and confirmed that IPA could up-regulate the expression of TCF7 and promote the differentiation of Tpex subset through in vitro cell experiments. At the same time, in vivo animal experiments confirmed the important role of TCF7 in IPA-promoting immunotherapy. Next, scATACseq, CUT Tag and ChIP were used to confirm that IPA regulated the transcription of TCF7 through H3K27 acetylation, promoted the expression of TCF7, up-regulated the proportion of Tpex subsets, and enhanced the effect of immunotherapy. The effect of IPA-enhanced immunotherapy was identified in multiple tumor model and organoid models. Collectively, this paper identified a microbial metabolite-immune regulatory pathway and suggest a potential microbial-based adjuvant approach to improve the responsiveness of immunotherapy.
DOI: 10.1016/j.cell.2024.02.022
Editor & Reviewer: Yanwen Zhu
