The human secretome and membrane proteome are a large source of cancer biomarkers. Membrane‐bound and secreted proteins are promising targets for many clinically approved drugs, including for the treatment of tumours. Here, we report a deep systematic analysis of 957 adenocarcinomas of the oesophagus, stomach, colon and rectum to examine the cancer‐associated human secretome and membrane proteome of gastrointestinal tract adenocarcinomas (GIACs). Transcriptomic data from these GIACs were applied to an innovative majority decision‐based algorithm. We quantified significantly expressed protein‐coding genes. Interestingly, we found a consistent pattern in a small group of genes found to be overexpressed in GIACs, which were associated with a cytokine–cytokine interaction pathway (CCRI) in all four cancer subtypes. These CCRI associated genes, which spanned both one secretory and one membrane isoform were further analysed, revealing a putative biomarker, interleukin‐1 receptor accessory protein (IL1RAP), which indicated a poor overall survival, a positive correlation with cancer stemness and a negative correlation with several kinds of T cells. These results were further validated in vitro through the knockdown of IL1RAP in two human gastric carcinoma cell lines, which resulted in a reduced indication of cellular proliferation, migration and markers of invasiveness. Following IL1RAP silencing, RNA seq results showed a consistent pattern of inhibition related to CCRI, proliferation pathways and low infiltration of regulatory T cells (Tregs) and CD8 naive cells. The significance of the human secretome and membrane proteome is elucidated by these findings, which indicate IL1RAP as a potential candidate biomarker for cytokine‐mediated cancer immunotherapy in gastric carcinoma.

Background. The dysregulated PI3K/AKT/mTOR pathway acts as the main regulator of tumorigenesis in hepatocellular carcinoma (HCC). Aim. Here, we identify the prognostic significance of PI3K/AKT/mTOR pathway-associated genes (PAGs) as well as their putative signature based on PAGs in an HCC patient's cohort. Methods. The transcriptomic data and clinical feature sets were queried to extract the putative prognostic signature. Results. We identified nine PAGs with different expressions. GO and KEGG indicated that these differentially expressed genes were associated with various carcinogenic pathways. Based on the signature-computed median risk score, we categorized the patients into groups of low risk and high risk. The survival time for the low-risk group is longer than that of the high-risk group in Kaplan-Meier (KM) curves. The prognostic value of risk score (ROC = 0:736) of receiver operating characteristic (ROC) curves performed better in comparison to that of other clinicopathological features. In both the GEO database and ICGC database, these outcomes were verified. The predictions of the overall survival rates in HCC patients of 1 year, 3 years, and 5 years can be obtained separately from the nomogram. The risk score was associated with the immune infiltrations of CD8 T cells, activated CD4 memory T cells, and follicular helper T cells, and the expression of immune checkpoints (PD-1, TIGIT, TIM-3, BTLA, LAG-3, and CTLA4) was positively relevant to the risk score. The sensitivity to several chemotherapeutic drugs can also be revealed by the signature. CDK1, PITX2, PRKAA2, and SFN were all upregulated in the tumor tissue of clinical samples. Conclusion. A putative and differential dataset-validated prognostic signature on the basis of integrated bioinformatic analysis was established in our study, providing the immunotherapeutic targets as well as the personalized treatment in HCC with neoteric insight.

Background: Interleukin-7 receptor (IL7R) signaling is critical for T-cell survival, homeostasis, and immune function, but the therapeutic potential of increasing IL7R expression through messenger RNA (mRNA) delivery remains poorly defined. We investigated whether IL7R mRNA therapy could enhance antitumor immunity and improve tumor control in preclinical cancer models. Methods: IL7R mRNA formulated in lipid nanoparticles (LNPs) was administered by combined intratumoral and intravenous injection in syngeneic B16 melanoma and Lewis lung carcinoma (LLC) models, with empty LNPs included as vehicle controls. Therapeutic efficacy, IL7R expression, immune responses, transcriptomic remodeling, T-cell receptor (TCR) repertoire changes, and treatment tolerability were evaluated using complementary molecular, immunological, and sequencing approaches. Results: IL7R mRNA treatment increased IL7R transcript and protein levels in tumor-bearing mice, whereas empty LNPs did not produce comparable increases. Treatment increased tumor-infiltrating CD8 T-cell frequencies, suppressed tumor growth and prolonged survival in both B16 and LLC models; empty LNP controls did not reproduce the therapeutic effect. Cytokine and transcriptomic analyses showed treatment-associated activation of inflammatory, T-cell, interferon, and antigen-receptor signaling programs. TCR sequencing further demonstrated increased repertoire diversity and reduced clonal dominance following IL7R mRNA treatment. No obvious body-weight loss or marked changes in serum alanine aminotransferase, aspartate aminotransferase, or creatinine were observed under the tested conditions. Conclusions: IL7R mRNA therapy increases IL7R expression and is associated with enhanced T-cell antitumor responses, tumor growth suppression, improved survival, and remodeling of the tumor immune environment. These findings support further mechanistic and preclinical evaluation of IL7R mRNA-based cancer immunotherapy.