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Introduction The aim of this study was to investigate the role and mechanism of long non-coding RNA (lncRNA) TRG-AS1 in mediating the proliferation, invasion and migration of lung cancer cells as well lung tumor growth. Methods Firstly, the expression levels of TRG-AS1, miR-224-5p in lung cancer tissues or cells were quantified by quantitative real-time PCR. Western blot analysis was conducted to measure the expression levels of protein SMAD4. CCK-8 assay, wound healing assay and transwell assay were conducted to evaluate cell proliferation, migration and invasion, respectively. The interaction between TRG-AS1 and miR-224-5p was predicted by bioinformatics analysis. Dual-luciferase assay and RNA pull-down assay were performed to further confirm their interaction. In addition, the interaction between miR-224-5p and SMAD4 was detected by RIP assay. Results The results showed that TRG-AS1 was highly upregulated and miR-224-5p was downregulated in lung cancer. A negative correlation was found between TRG-AS1 and miR-224-5p. Furthermore, upregulation of TRG-AS1 promoted cell proliferation and invasion, while overexpression of miR-224-5p attenuated the effects of TRG-AS1. The downstream protein SMAD4 played an important role. In vivo study showed that knockdown of TRG-AS1 effectively retarded tumor growth. Discussion Our data suggested that the TRG-AS1/miR-224-5p/SMAD4 axis may be a potential therapeutic target in lung cancer.

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4553 Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved with the advent of either dual immune checkpoint inhibition (ICI) or in combination with Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor. Gut microbiota plays a central role in developing local and systemic immunity, with potential influence in controlling anti-tumor immune response in cancer patients treated with ICI. We hypothesize that FMT from healthy donors given before immunotherapy will establish a more resilient gut microbiota, reducing the treatment toxicity and improving response to therapy. PERFORM is an ongoing phase I study evaluating the safety of FMT and immunotherapy combination in first-line (1L) mRCC, and assessing whether FMT will prevent or mitigate immune-related adverse events (irAE). Methods: Eligible patients with untreated mRCC received a full dose and 2 supportive FMT procedures prior to the first 3 cycles of doublet ICI or in combination with VEGF-TKI. Primary endpoint is the feasibility and safety of combining FMT using intestinal bacteria existing in the stool of healthy donors with immunotherapy. Secondary endpoints include incidence of irAEs, objective response rate (ORR; RECIST v1.1), and changes in pts microbiome and immune profile post-FMT. We included a preliminary analysis of the first 10 patients. Results: 10 patients received FMT and doublet ICI therapy (10 ongoing). 8/10 (80%) patients were male. Median Age: 59.5 (53-71) years-old. Most common histology was clear cell RCC (90%) and all patients had an intermediate or poor-risk disease. 93.3% of planned FMT were administered. No dose-limiting toxicities due to FMT were observed. Median (range) follow-up was 5.5 (1–22) months. 4 patients (40%) discontinued treatment due to irAEs: colitis (n = 3), arthritis (n = 1). IrAEs were reported in 8 (80%) patients, including diarrhea (n = 6; 60%) and skin rash (n = 2, 20%). Grade 3/4 AEs were experienced by 6 (60%) patients, including colitis (n = 4, 40%). ORR was confirmed in 4/9 patients (44%; 95% CI, 30–60); 1 (11%) partial response. Microbiota and immune analysis data to be presented. Conclusions: The role of microbiome modification in preventing immune-related toxicities by adding FMT to ICI therapy was associated with a safety profile in unselected 1L mRCC and promising clinical efficacy data. Further prospective studies to examine the changes in the immune and microbiota profiles to determine biomarkers related to healthy outcomes/less frequent toxicities in patients receiving immunotherapy are warranted. Clinical trial information: NCT04163289.

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