Galectin-7 Induction by EHMT2 Inhibition Enhances Immunity in Microsatellite Stability Colorectal Cancer.

BACKGROUND & AIMS: Although immunotherapy shows substantial advancement in colorectal cancer (CRC) with microsatellite instability high, it has limited efficacy for CRC with microsatellite stability (MSS). Identifying combinations that reverse immune suppression and prime MSS tumors for current immunotherapy approaches remains an urgent need. METHODS: An in vitro CRISPR screen was performed using coculture models of primary tumor cells and autologous immune cells from MSS CRC patients to identify epigenetic targets that could enhance immunotherapy efficacy in MSS tumors. RESULTS: We revealed EHMT2, a histone methyltransferase, as a potential target for MSS CRC. EHMT2 inhibition transformed the immunosuppressive microenvironment of MSS tumors into an immunomodulatory one by altering cytokine expression, leading to T-cell-mediated cytotoxicity activation and improved responsiveness to anti-PD1 treatment. We observed galectin-7 up-regulation upon EHMT2 inhibition, which converted a "cold" MSS tumor environment into a T-cell-inflamed one. Mechanistically, CHD4 repressed galectin-7 expression by recruiting EHMT2 to form a cotranscriptional silencing complex. Galectin-7 administration enhanced anti-PD1 efficacy in MSS CRC, serving as a potent adjunct cytokine therapy. CONCLUSIONS: Our findings suggest that targeting the EHMT2/galectin-7 axis could provide a novel combination strategy for immunotherapy in MSS CRC.

Biological informed graph neural network for tumor mutation burden prediction and immunotherapy-related pathway analysis in gastric cancer.

Tumor mutation burden (TMB) has emerged as an essential biomarker for assessing the efficacy of cancer immunotherapy. However, due to the inherent complexity of tumors, TMB is not always correlated with the responsiveness of immune checkpoint inhibitors (ICIs). Thus, refining the interpretation and contextualization of TMB is a requisite for enhancing clinical outcomes. In this study, we conducted a comprehensive investigation of the relationship between TMB and multi-omics data across 33 human cancer types. Our analysis revealed distinct biological changes associated with varying TMB statuses in STAD, COAD, and UCEC. While multi-omics data offer an opportunity to dissect the intricacies of tumors, extracting meaningful biological insights from such massive information remains a formidable challenge. To address this, we developed and implemented the PGLCN, a biologically informed graph neural network based on pathway interaction information. This model facilitates the stratification of patients into subgroups with distinct TMB statuses and enables the evaluation of driver biological processes through enhanced interpretability. By integrating multi-omics data for TMB prediction, our PGLCN model outperformed previous traditional machine learning methodologies, demonstrating superior TMB status prediction accuracy (STAD AUC: 0.976 ± 0.007; COAD AUC: 0.994 ± 0.007; UCEC AUC: 0.947 ± 0.023) and enhanced interpretability (BA-House: 1.0; BA-Community: 0.999; BA-Grid: 0.994; Tree-Cycles: 0.917; Tree-Grids: 0.867). Furthermore, the biological interpretability inherent to PGLCN identified the Toll-like receptor family and DNA repair pathways as potential combined biomarkers in conjunction with TMB status in gastric cancer. This finding suggests a potential synergistic targeting strategy with immunotherapy for gastric cancer, thus advancing the field of precision oncology.

RNA-binding protein RALY reprogrammes mitochondrial metabolism via mediating miRNA processing in colorectal cancer.

OBJECTIVE: Dysregulated cellular metabolism is a distinct hallmark of human colorectal cancer (CRC). However, metabolic programme rewiring during tumour progression has yet to be fully understood. DESIGN: We analysed altered gene signatures during colorectal tumour progression, and used a complex of molecular and metabolic assays to study the regulation of metabolism in CRC cell lines, human patient-derived xenograft mouse models and tumour organoid models. RESULTS: We identified a novel RNA-binding protein, RALY (also known as hnRNPCL2), that is highly associated with colorectal tumour aggressiveness. RALY acts as a key regulatory component in the Drosha complex, and promotes the post-transcriptional processing of a specific subset of miRNAs (miR-483, miR-676 and miR-877). These miRNAs systematically downregulate the expression of the metabolism-associated genes (ATP5I, ATP5G1, ATP5G3 and CYC1) and thereby reprogramme mitochondrial metabolism in the cancer cell. Analysis of The Cancer Genome Atlas (TCGA) reveals that increased levels of RALY are associated with poor prognosis in the patients with CRC expressing low levels of mitochondrion-associated genes. Mechanistically, induced processing of these miRNAs is facilitated by their N6-methyladenosine switch under reactive oxygen species (ROS) stress. Inhibition of the m6A methylation abolishes the RALY recognition of the terminal loop of the pri-miRNAs. Knockdown of RALY inhibits colorectal tumour growth and progression in vivo and in organoid models. CONCLUSIONS: Collectively, our results reveal a critical metabolism-centric role of RALY in tumour progression, which may lead to cancer therapeutics targeting RALY for treating CRC.

A versatile UCST-type composite microsphere for image-guided chemoembolization and photothermal therapy against liver cancer.

The development of novel chemoembolization agents to improve the treatment efficacy of transarterial chemoembolization (TACE) against liver cancer remains an urgent need in clinical practice. Herein, a versatile composite microsphere with upper critical solution temperature (UCST) properties was prepared to encapsulate polydopamine coated superparamagnetic iron oxide nanoparticles (SPION@PDA) and doxorubicin for simultaneous chemoembolization and photothermal therapy. The microspheres were spherical with an average diameter of 100-300 µm and exhibited favorable drug loading capability as well as strong photothermal effect. Strikingly, synergistic enhancement of photothermal therapy and chemotherapy against chemoresistant liver cancer cells was achieved. The in vivo therapeutic efficacy and safety evaluations were performed using rabbit VX2 liver tumor models. It was revealed that a single treatment of the combination of TACE and photothermal procedure resulted in 87.5% complete response and 12.5% partial response for the microsphere group, whereas all tumors in the control group progressed rapidly. Contrast-enhanced computed tomography (CT) evaluation indicated that the tumor diameter decreased by 91.5% after treatment, while that in the control group increased by 86.5%. The pathology-proven tumor necrotic rate was 87.2%, which significantly surpassed that of 65.2% in the control group. Furthermore, serum liver enzyme and biochemical studies indicated a temporary liver injury which can be fully recovered. Our findings demonstrated that this microsphere may be advantageous for enhancing therapeutic efficacy of TACE against liver cancer.

Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance.

Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS, NRAS, and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA, PTEN, TP53, MET, HER3, IRS2, FGFR1, and MAP2K1, the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.

Fatty Acid Oxidation Controls CD8+ Tissue-Resident Memory T-cell Survival in Gastric Adenocarcinoma.

The success of checkpoint inhibitors in cancer treatment is associated with the infiltration of tissue-resident memory T (Trm) cells. In this study, we found that about 30% of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment of gastric adenocarcinoma were CD69+CD103+ Trm cells. Trm cells were low in patients with metastasis, and the presence of Trm cells was associated with better prognosis in patients with gastric adenocarcinoma. Trm cells expressed high PD-1, TIGIT, and CD39 and represented tumor-reactive TILs. Instead of utilizing glucose, Trm cells relied on fatty acid oxidation for cell survival. Deprivation of fatty acid resulted in Trm cell death. In a tumor cell-T-cell coculture system, gastric adenocarcinoma cells outcompeted Trm cells for lipid uptake and induced Trm cell death. Targeting PD-L1 decreased fatty acid binding protein (Fabp) 4 and Fabp5 expression in tumor cells of gastric adenocarcinoma. In contrast, the blockade of PD-L1 increased Fabp4/5 expression in Trm cells, promoting lipid uptake by Trm cells and resulting in better survival of Trm cells in vitro and in vivo. PD-L1 blockade unleashed Trm cells specifically in the patient-derived xenograft (PDX) mice. PDX mice that did not respond to PD-L1 blockade had less Trm cells than responders. Together, these data demonstrated that Trm cells represent a subset of TILs in the antitumor immune response and that metabolic reprogramming could be a promising way to prolong the longevity of Trm cells and enhance antitumor immunity in gastric adenocarcinoma.