Achieving Immune Activation by Suppressing the IDO1 Checkpoint with Sono-Targeted Biobromination for Antitumor Combination Immunotherapy.

Indoleamine-2,3-dioxygenase-1 (IDO1) pathogenically suppresses immune cell infiltration and promotes tumor cell immune escape by overmetabolizing tryptophan to N-formyl kynurenine in the tumor microenvironment (TME). However, it remains challenging for IDO1 immune checkpoint inhibitors to achieve a significant potency of progression-free survival. Here, we developed a breakthrough in IDO1 inhibition by sono-targeted biobromination reaction using immunostimulating hypobromic-P-phenylperoxydibenzoic acid-linked metallic organic framework nanomedicine (H-MOF NM) to remodel the TME from debrominated hypoxia into hypobromated normoxia and activate the IDO1 immune pathway with in vitro and in vivo remarkable antitumor efficacy. H-MOF NM contains Br+ and O- active ingredients with an enlarged band gap to deactivate IDO1 through an innovative biochemical mechanism, taking control over brominating IDO1 amino acid residues at the active sites in the remodeled TME and subsequently activating the immune response, including DC maturation, T-cell activation, and macrophage polarization. Importantly, the H-MOF NM achieves multiple immune responses with high tumor regression potency by combination sono-immunotherapy. This study describes an excellent IDO1 inhibition strategy through the development of immune biobrominative H-MOF nanomedicine and highlights efficient combination immunotherapy for tumor treatment.

The next bastion to be conquered in immunotherapy: microsatellite stable colorectal cancer.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and its incidence continues to rise, particularly in developing countries. The advent of immune checkpoint inhibitors (ICIs) has represented a significant advancement in CRC treatment. Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) serves as a biomarker for immunotherapy, with dMMR/MSI-H CRC exhibiting significantly better response rates to immunotherapy compared to proficient mismatch repair (pMMR)or microsatellite stable (MSS) CRC. While some progress has been made in the treatment of pMMR/MSS CRC in recent years, it remains a challenging issue in clinical practice. The tumor microenvironment (TME) plays a crucial role not only in the development and progression of CRC but also in determining the response to immunotherapy. Understanding the characteristics of the TME in pMMR/MSS CRC could offer new insights to enhance the efficacy of immunotherapy. In this review, we provide an overview of the current research progress on the TME characteristics and advancements in immunotherapy for pMMR/MSS CRC.

Driving neoantigen-based cancer vaccines for personalized immunotherapy into clinic: A burdensome journey to promising land.

As tumor-specific antigens, neoantigens are ideal targets for immunotherapy, and their value in the clinical application has been noted and appreciated recently. Neoantigen-based cancer vaccine is also emerging as a promising novel therapeutic modality. Tumor neoantigen vaccines work by eliciting specific autogenous immune responses via inoculation of neoantigens in cancer patients to eliminate tumors. However, despite the good clinical efficacy and great potential of neoantigen vaccines, some challenges remain to be addressed. This review aims to illustrate the generation and development of neoantigen-specific immune responses, summarize the preparation technology and recent clinical research findings of neoantigen-based cancer vaccines, analyze the main challenges faced by neoantigen vaccines and present possible solutions. This review may provide new insights and foundation for future research and development of cancer vaccines and accelerate their clinical application process, and thereby benefit more patients with advanced tumors by early interventions.

Synergistic Therapeutic Effects of Low Dose Decitabine and NY-ESO-1 Specific TCR-T Cells for the Colorectal Cancer With Microsatellite Stability.

Patients of colorectal cancer (CRC) with microsatellite stability (MSS) show poor clinical response and little beneficial result from the immune-checkpoint inhibitors, due to the 'cold' tumor microenvironment. Meanwhile, decitabine can drive the 'cold' microenvironment towards 'hot' in multiple ways, such as upregulating the tumor associated antigen (TAA) and human leukocyte antigen (HLA) molecular. NY-ESO-1, one of the most important TAAs, can be observably induced in tumors by low dose decitabine, and present itself as ideal targets for antigen specific T cell receptor engineered T (TCR-T) cells. We innovatively used a synergistic tactic, combining decitabine and NY-ESO-1 specific TCR-T cells, for fighting the MSS CRC. Firstly, we confirmed the lysing effect of the NY-ESO-1 TCR-T cells on the NY-ESO-1+ and HLA-A2+ cells in vitro and in vivo. In A375 tumor-bearing mice, the results showed that NY-ESO-1 TCR-T cell therapy could inhibit A375 tumor growth and prolonged the survival time. Furthermore, the synergistic effect of decitabine and NY-ESO-1 TCR-T cells was shown to induce an even higher percentage of tumor cells being lysed in vitro than other control groups, and more potent tumor inhibition and longer survival time were observed in vivo. The innovative synergistic therapeutic strategy of decitabine and TCR-T cells for the CRC with MSS may be also effective in the treatment of other epithelial malignancies. Decitabine may likewise be adopted in combination with other cellular immunotherapies.

Correction to: Low-dose decitabine enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by re-modulating the tumor microenvironment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Low-dose decitabine enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by re-modulating the tumor microenvironment.

PD-1 blockade has demonstrated impressive clinical outcomes in colorectal cancers that have high microsatellite instability. However, the therapeutic efficacy for patients with tumors with low microsatellite instability or stable microsatellites needs further improvement. Here, we have demonstrated that low-dose decitabine could increase the expression of immune-related genes such as major histocompatibility complex genes and cytokine-related genes as well as the number of lymphocytes at the tumor site in CT26 colorectal cancer-bearing mice. A more significant inhibition of tumor growth and a prolongation of survival were observed in the CT26 mouse model after treatment with a combination of PD-1 blockade and decitabine than in mice treated with decitabine or PD-1 blockade alone. The anti-tumor effect of the PD-1 blockade was enhanced by low-dose decitabine. The results of RNA sequencing and whole-genome bisulfite sequencing of decitabine-treated CT26 cells and tumor samples with microsatellite stability from the patient tumor-derived xenograft model have shown that many immune-related genes, including antigen-processing and antigen-presenting genes, were upregulated, whereas the promoter demethylation was downregulated after decitabine exposure. Therefore, decitabine-based tumor microenvironment re-modulation could improve the effect of the PD-1 blockade. The application of decitabine in PD-1 blockade-based immunotherapy may elicit more potent immune responses, which can provide clinical benefits to the colorectal cancer patients with low microsatellite instability or stable microsatellites.

Meta-analysis of chemotherapy and dendritic cells with cytokine-induced killer cells in the treatment of non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is one of the most fatal cancers, which leads to large number of people dead. Followed by surgery, chemotherapy and radiotherapy, chemotherapy combined dendritic cells with cytokine-induced killer cells (DC-CIK) immunotherapy has been applied in NSCLC for some time, but little consistent beneficial results are provided. So, it is essential to weigh the pros and cons of the new therapeutic method. METHODS: We searched the randomized controlled trials of NSCLC mainly by PubMed database. Terms combination of "cytokine-induced killer cells", "tumor" and "cancer" were used. After evaluating the heterogeneity of selected studies, then we performed the meta-analysis. Pooled risk ratios (RRs) were estimated and 95% confidence intervals (CIs) were calculated using a fixed-effect model. Sensitivity analysis was also performed. RESULTS: Six eligible trials were enrolled. Efficiency and safety of chemotherapy followed by DC-CIK immunotherapy (experimental group) and chemotherapy alone (control group) were compared. 1-year overall survival (OS) (P=0.02) and progression free survival (PFS) (P=0.005) in the experimental group were significantly increased compared with the control. Disease control rate (DCR) (P=0.006) rose significantly in experimental group. However, no significant differences between the two groups were observed in 2-year OS (P=0.21), 2-year PFS (P=0.10), overall response rate (ORR) (P=0.76) and partial response (PR) (P=0.22). Temporary fever, anemia, leukopenia and nausea were the four major adverse events (AEs) treated by chemotherapy. The incidence of anemia, leukopenia and nausea in the experimental group was obviously lower than the control group. Temporary fever rate was higher in experimental group than that in the control, but could be alleviated by taking sufficient rest. CONCLUSIONS: Chemotherapy combined with DC-CIK immunotherapy showed superiority in DCR, 1-year OS and PFS, and no more AEs appeared, however, there was no significant improvement in ORR, PR, 2-year OS and PFS. As a whole, the combination therapy is safer but modest in efficacy for advanced NSCLC patients.