Analysis of Interleukin-1 Signaling Alterations of Colon Adenocarcinoma Identified Implications for Immunotherapy.

Immune checkpoint inhibitors (ICIs) have made breakthrough progress in the treatment of various malignant tumors. However, only some patients receiving ICIs obtain long-lasting clinical effects, and some patients still do not achieve remission. Improving the treatment benefits of this part of the population has become a concern of clinicians. IL-1 signaling plays an important role in the tumor microenvironment (TME). However, the relationship between the IL-1 signaling mutation status and the prognosis of colon adenocarcinoma (COAD) patients receiving ICIs has not been reported. We downloaded the data of a COAD cohort receiving ICIs, including prognostic data and mutation data. Additionally, we downloaded the data of a COAD cohort from The Cancer Genome Atlas (TCGA) database, including clinical data, expression data and mutation data. Gene set enrichment analysis (GSEA) was used to assess differences in the activity of some key physiological pathways between the IL-1 signaling mutated-type (IL-1-MT) and IL-1 signaling wild-type (IL-1-WT) groups. The CIBERSORT algorithm was used to evaluate the contents of immune cells in the TME of COAD patients. The multivariate Cox regression model results suggested that IL-1-MT can be used as an independent predictor of a better prognosis in COAD patients receiving ICIs (P = 0.03, HR = 0.269, 95% CI: 0.082-0.883). Additionally, IL-1-MT COAD patients had significantly longer overall survival (OS) (log-rank P = 0.015). CIBERSORT analysis showed that the IL-1-MT group had high infiltration levels of activated dendritic cells (DCs), M1 macrophages, neutrophils, activated natural killer (NK) cells, activated CD4+ memory T cells and CD8+ T cells. Similarly, the IL-1-MT group had significantly upregulated immunogenicity, including in terms of the tumor mutation burden (TMB), neoantigen load (NAL) and number of mutations in DNA damage repair (DDR) signaling. GSEA showed that the IL-1-MT group was highly enriched in the immune response and proinflammatory mediators. Additionally, the expression levels of immune-related genes, immune checkpoint molecules and immune-related signatures were significantly higher in the IL-1-MT group than in the IL-1-WT group. IL-1-MT may be an independent predictor of a good prognosis in COAD patients receiving ICIs, with significantly longer OS in IL-1-MT COAD patients. Additionally, IL-1-MT was associated with significantly increased immunogenicity, activated immune cell and inflammatory mediator levels and immune response-related scores.

Zhou X ，Liu Y ，Xiang J ，Wang Y ，Wang Q ，Xia J ，Chen Y ，Bai Y ... -  《Frontiers in Immunology》

Comprehensive Analysis Identifies PI3K/Akt Pathway Alternations as an Immune-Related Prognostic Biomarker in Colon Adenocarcinoma Patients Receiving Immune Checkpoint Inhibitor Treatment.

In recent years, immune checkpoint inhibitors (ICIs) have attracted widespread attention and made breakthroughs in progress towards the treatment of various cancers. However, ICI therapy is selective, and its effects on many patients are not ideal. It is therefore critical to identify prognostic biomarkers of response to ICI therapy. The PI3K/Akt pathway plays important roles in tumor formation and metastasis. However, there are no published reports clarifying the relationship between PI3K/Akt pathway mutations and prognosis for colon adenocarcinoma (COAD) patients receiving immunotherapy. We collected data from a COAD cohort from The Cancer Genome Atlas (TCGA) database, including whole-exome sequencing (WES) data, RNA-seq data, and clinical data. We also collected data, including clinical prognosis and targeted sequencing data, from a cohort of COAD patients receiving immunotherapy. We collected 50 COAD patients (Local-COAD) from the Zhujiang Hospital of Southern Medical University and performed targeted sequencing. We analyzed the effects of PI3K/Akt pathway mutations on the patients' clinical prognosis, immunogenicity, and immune microenvironments. Gene set enrichment analysis (GSEA) was used to analyze the significantly upregulated and downregulated signaling pathways. We used these results to hypothesize potential mechanisms by which PI3K/Akt mutations could affect the prognosis of COAD patients. Univariate and multivariate Cox analyses and Kaplan-Meier (KM) survival curves showed that patients with PI3K-Akt mutations had better overall survival (OS) than those without PI3K-Akt mutations. Genes with significant mutation rates in the two cohorts were screened by panoramic view. CIBERSORT was used to analyze changes in 22 types of immune cells to identify immune activated cells. Similarly, patients in the PI3K/Akt-mutated type (PI3K/Akt-MT) group had significantly increased immunogenicity, including increases in tumor mutation burden (TMB), neoantigen load (NAL), and MANTIS score. Using GSEA, we identified upregulated pathways related to immune response. PI3K/Akt pathway mutation status can be used as an independent predictor of response to ICI treatment in COAD patients. PI3K/Akt mutations are correlated with improved OS, higher immunogenicity, greater immune response scores, and increases in activated immune cells.

Lin A ，Gu T ，Hu X ，Zhang J ，Luo P ... -  《-》

Exploration of the relationship between tumor mutation burden and immune infiltrates in colon adenocarcinoma.

Background: Tumor mutation burden (TMB) was correlated with the immunotherapeutic response in various malignancies. We aimed to evaluate the TMB immune signature in colon adenocarcinoma (COAD). Methods: Gene expression profile, mutation and clinical data of COAD patients were obtained from The Cancer Genome Atlas (TCGA) database. The samples were divided into high and low TMB level groups to identify differentially expressed genes (DEGs). Functional enrichments analyzes were performed to identify the biological functions of the DEGs. Then, immune cell infiltration signatures were calculated by the CIBERSORT algorithm. Finally, Cox proportional hazard model was constructed to estimate the prognostic value of the identified immune-related genes. Results: Gene set enrichment analysis in the high-TMB level group showed that DEGS were enriched in immune-related pathways, such as antigen processing and presentation, Toll-like receptor signaling and natural killer cell-mediated cytotoxicity. A higher infiltration level of CD8+ T cells, CD4+ T cells, activated NK cells , M1 Macrophages and T follicular helper cells was observed in the high-TMB level group. Furthermore, a Cox regression model combined with survival analysis based on the expression level of four identified prognostic genes was constructed, validated anf revealed that higher risk-score levels conferred poor survival outcomes in COAD patients. Conclusions: Our data demonstrate that the high TMB levels are associated with an immune signature in COAD and deepen the molecular understanding of TMB function in tumor immunotherapy.

Ouyang R ，Li Z ，Peng P ，Zhang J ，Liu J ，Qin M ，Huang J ... -  《International Journal of Medical Sciences》

To explore the prognostic characteristics of colon cancer based on tertiary lymphoid structure-related genes and reveal the characteristics of tumor microenvironment and drug prediction.

In order to construct a prognostic evaluation model of TLS features in COAD and better realize personalized precision medicine in COAD. Colon adenocarcinoma (COAD) is a common malignant tumor of the digestive system. At present, there is no effective prognostic marker to predict the prognosis of patients. Tertiary lymphoid structure (TLS) affects cancer progression by regulating immune microenvironment. Mining COAD biomarkers based on TLS-related genes helps to improve the prognosis of patients. In order to construct a prognostic evaluation model of TLS features in COAD and better realize personalized precision medicine in COAD. The mRNA expression data and clinical information of COAD and adjacent tissues were downloaded from the Cancer Genome Atlas database. The differentially expressed TLS-related genes of COAD relative to adjacent tissues were obtained by differential analysis. TLS gene co-expression analysis was used to mine genes highly related to TLS, and the intersection of the two was used to obtain candidate genes. Univariate, LASSO, and multivariate Cox regression analysis were performed on candidate genes to screen prognostic markers to construct a risk assessment model. The differences of immune characteristics were evaluated by ESTIMATE, ssGSEA and CIBERSORT in high and low risk groups of prognostic model. The difference of genomic mutation between groups was evaluated by tumor mutation burden score. Screening small molecule drugs through the GDSC library. Finally, a nomogram was drawn to evaluate the clinical value of the prognostic model. Seven TLS-related genes ADAM8, SLC6A1, PAXX, RIMKLB, PTH1R, CD1B, and MMP10 were screened to construct a prognostic model. Survival analysis showed that patients in the high-risk group had significantly lower overall survival rates. Immune microenvironment analysis showed that patients in the high-risk group had higher immune indicators, indicating higher immunity. The genomic mutation patterns of the high-risk and low-risk groups were significantly different, especially the KRAS mutation frequency was significantly higher in the high-risk group. Drug sensitivity analysis showed that the low-risk group was more sensitive to Erlotinib, Savolitinib and VE _ 822, which may be used as a potential drug for COAD treatment. Finally, the nomogram constructed by pathological features combined with RiskScore can accurately evaluate the prognosis of COAD patients. This study constructed and verified a TLS model that can predict COAD. More importantly, it provides a reference standard for guiding the prognosis and immunotherapy of COAD patients.

Wang Z ，Niu D 《Scientific Reports》

Effect of TTN Mutations on Immune Microenvironment and Efficacy of Immunotherapy in Lung Adenocarcinoma Patients.

Immune checkpoint inhibitors (ICIs) effectively treat lung adenocarcinoma (LUAD) with fewer side effects. However, for LUAD patients, the lack of predictive markers for ICIs makes their clinical benefits less than ideal. Despite reports suggesting that a TTN (titin) mutation plays an important role in immunotherapy of solid tumors and gastric cancer, the relationship between the TTN mutation and LUAD immunotherapy has not been determined. We collected a LUAD cohort with whole-exome sequencing (WES) and immunotherapy prognosis. The ICI cohort was used to explore the relationship between TTN mutation status and prognosis. Then, the Cancer Genome Atlas (TCGA)-LUAD and Chen-LUAD cohorts were downloaded from the cbioportal website. We also used CIBERSORT, gene-set enrichment analysis (GSEA), and single-sample GSEA (ssGSEA) to evaluate the proportion of immune cells and the degree of pathway activation in LUAD patients, respectively. DDR signaling pathways obtained from the Molecular Signatures Database (MSigDB), tumor mutation burden (TMB), and NAL were used to evaluate the immunogenicity of LUAD patients. In the ICI cohort, TTN-mutant (TTN-MT) had significantly longer overall survival (OS) than TTN-wildtype (TTN-WT) (P = 0.009). Univariate and multivariate COX models showed that TTN mutation status can independently predict immunotherapy prognosis. Notably, the results of tumor immune microenvironment (TIME) analysis showed that TTN-MT patients had inflammatory TIME, which showed enriched activated immune cells and higher immune scores. Immunogenicity analysis showed higher immunogenicity in TTN-MT patients, which indicated high levels of gene mutations in TMB, NAL, and DDR pathways. GSEA and ssGSEA results showed that TTN-MT was substantially enriched in chemokine secretion, inflammatory factor secretion, and antigen presentation. Some pathways related to immunosuppression and immune depletion were significantly downregulated. TTN-MT is associated with significantly prolonged OS in LUAD patients. Additionally, TTN-MT is related to high immunogenicity and inflammatory TIME, suggesting that TTN-MT may be a potential predictive marker for patients with LUAD to accept ICIs.

Wang Z ，Wang C ，Lin S ，Yu X ... -  《Frontiers in Oncology》