TP53 mutation is the most common mutation in hepatocellular carcinoma (HCC), and it affects the progression and prognosis of HCC. We investigated how TP53 mutation regulates the HCC immunophenotype and thus affects the prognosis of HCC. We investigated TP53 mutation status and RNA expression in different populations and platforms and developed an immune prognostic model (IPM) based on immune-related genes that were differentially expressed between TP53WT and TP53MUT HCC samples. Then, the influence of the IPM on the immune microenvironment in HCC was comprehensively analysed. TP53 mutation resulted in the downregulation of the immune response in HCC. Thirty-seven of the 312 immune response-related genes were differentially expressed based on TP53 mutation status. An IPM was established and validated based on 865 patients with HCC to differentiate patients with a low or high risk of poor survival. A nomogram was also established for clinical application. Functional enrichment analysis showed that the humoral immune response and immune system diseases pathway represented the major function and pathway, respectively, related to the IPM genes. Moreover, we found that the patients in the high-risk group had higher fractions of T cells follicular helper, T cells regulatory (Tregs) and macrophages M0 and presented higher expression of CTLA-4, PD-1 and TIM-3 than the low-risk group. TP53 mutation is strongly related to the immune microenvironment in HCC. Our IPM, which is sensitive to TP53 mutation status, may have important implications for identifying subgroups of HCC patients with low or high risk of unfavourable survival. FUND: This work was supported by the International Science and Technology Cooperation Projects (2016YFE0107100), the Capital Special Research Project for Health Development (2014-2-4012), the Beijing Natural Science Foundation (L172055 and 7192158), the National Ten Thousand Talent Program, the Fundamental Research Funds for the Central Universities (3332018032), and the CAMS Innovation Fund for Medical Science (CIFMS) (2017-I2M-4-003 and 2018-I2M-3-001).

Long noncoding RNAs (lncRNAs) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression; therefore, lncRNAs are considered a major part of the competitive endogenous RNA (ceRNA) network and have attracted growing attention. The present study explored the regulatory mechanisms and functional roles of lncRNAs as ceRNAs in hepatocellular carcinoma (HCC) and their potential impact on HCC patient prognosis. In this study, we systematically studied the expression profiles and prognostic value of lncRNA, miRNA, and mRNA from a total of 838 HCC patients from five HCC cohorts (TCGA, GSE54236, GSE76427, GSE64041 and GSE14520). The TCGA, GSE54236 and GSE76427 HCC cohorts were utilized to establish a prognosis-related network of dysregulated ceRNAs by bioinformatics methods. The GSE64041 and GSE14520 HCC cohorts were utilized to verify the expression of candidate genes. In total, 721 lncRNAs, 73 miRNAs, and 1563 mRNAs were aberrantly expressed in HCC samples. A ceRNA network including 26 lncRNAs, four miRNAs, and six mRNAs specific to HCC was established. The survival analysis showed that four lncRNAs (MYCNOS, DLX6-AS1, LINC00221, and CRNDE) and two mRNAs (CCNB1 and SHCBP1) were prognostic biomarkers for patients with HCC in both the TCGA and GEO databases. The proposed ceRNA network may help elucidate the regulatory mechanism by which lncRNAs function as ceRNAs and contribute to the pathogenesis of HCC. Importantly, the candidate lncRNAs, miRNAs, and mRNAs involved in the ceRNA network can be further evaluated as potential therapeutic targets and prognostic biomarkers for HCC.

Gastrointestinal (GI) malignancies are the most prevalent tumors worldwide, with increasing incidence and mortality. Although surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy have led to significant advances in the treatment of GI cancer patients, overall survival is still low. Therefore, alternative strategies must be identified to improve patient outcomes. In the tumor microenvironment, tumor cells can escape the host immune response through the interaction of PD-1 and PD-L, which inhibits the function of T cells and tumor-infiltrating lymphocytes while increasing the function of immunosuppressive T regulatory cells. The use of an anti-PD-1/PD-L blockade enables reprogramming of the immune system to efficiently identify and kill tumor cells. In recent years, the efficacy of PD-1/PD-L blockade has been demonstrated in many tumors, and this treatment is expected to be a pan-immunotherapy for tumors. Here, we review the signaling pathway underlying the dysregulation of PD-1/PD-L in tumors, summarize the current clinical data for PD-1/PD-L inhibitors in GI malignancies, and discuss road toward precision immunotherapy in relation to PD-1/PD-L blockade. The preliminary data for PD-1/PD-L inhibitors are encouraging, and the precision immunotherapy of PD-1/PD-L inhibitors will be a viable and pivotal clinical strategy for GI cancer therapy.

Gastrointestinal (GI) malignant neoplasms have a high global incidence and treatment prospects for patients with advanced GI tumors are dismal. PD-1/PD-L1 inhibitors emerged as a frontline treatment for several types of cancer. However, the shortcomings of PD-1/PD-L1 inhibitors have been observed, including low objective response rates and acquired tumor resistance, especially in patients receiving PD-1/PD-L1 inhibitors as a single treatment. Accumulating evidence from clinical trials increasingly suggests that combined immunotherapies enhance therapeutic responses in patients with malignances, especially for GI tumors which have a complex matrix, and significant molecular and immunological differences. Preclinical and clinical studies suggest there are advantages to combined immunological regimens, which represents the next logical step in this field, although further research is necessary. This literature review explores the current limitations of monotherapies, before critically discussing the rationale behind combination regimens. Then, we provide a summary of the clinical applications for gastrointestinal cancers.

Background: Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of many cancers. However, the limited population that benefits from ICI therapy makes it necessary to screen predictive biomarkers for stratifying patients. Currently, many biomarkers, such as tumor mutational burden (TMB), have been used in the clinic as indicative biomarkers. However, some high-TMB patients with mutations in genes that are closely related to immunotherapeutic resistance are not sensitive to ICI therapy. Thus, there is a need to move beyond TMB and identify specific genetic determinants of the response to ICI therapy. In this study, we established a comprehensive mutation-based gene set across different tumor types to predict the efficacy of ICI therapy. Methods: We constructed and validated a mutational signature to predict the prognosis of patients treated with ICI therapy. Then, the underlying immune response landscapes of different subtypes were investigated with multidimensional data. Results: This study included genomic and clinical data for 12,647 patients. An eleven-gene mutation-based gene set was generated to divide patients into a high-risk group and a low-risk group in a training cohort (1572 patients with 9 types of cancers who were treated with ICI therapy). Validation was performed in a validation cohort (932 patients with 5 types of cancers who were treated with ICI therapy). Mutations in these 11 genes were associated with a better response to ICI therapy. In addition, the mutation-based gene set was demonstrated to be an independent prognostic factor after ICI therapy. We further explored the role of the immune context in determining the benefits of immunotherapy in 10,143 patients with 33 types of cancers and found distinct immune landscapes for the high- and low-risk groups. Conclusions: The mutation-based gene set developed in this study can be used to reliably predict survival benefit across cancers in patients receiving ICI therapy. The close interplay between the extrinsic and intrinsic immune landscapes in the identified patient subgroups and the subgroups’ differing responses to ICI therapy could guide immunotherapy treatment decisions for cancer patients.

Programmed death ligand 1/2 (PD-L1/PD-L2) expression has been established as a prognostic factor for various solid tumors and as a predictive factor for PD-1 blockade therapy, but scant data on its role in gallbladder cancer (GBC). The aims of this study were to assess the expression of PD-L1/PD-L2 and the density of CD8+ tumor-infiltrating lymphocytes (TIL) from GBC samples and to quantify the association between survival prognosis and these factors. CD8+ TILs density and the expression of PD-1, PD-L1, PD-L2 and CD133 were assessed using immunohistochemistry in tumor specimens from 66 patients with gallbladder adenocarcinoma. These indexes were correlated with the clinicopathological features. The rate of PD-L1-positive (PD-L1+) was 54%, which included 18% positivity in tumor cells, and 36% in peritumoral immune stroma. High CD8+ TIL density (CD8high) was observed in PD-L1+ GBC, and PD-L1+ was positively associated with PD-L2+ expression. Regarding prognostic factors, PD-L1+ expression was related to worse overall survival (OS), and CD8high indicated better OS and progression-free survival (PFS). The combination of CD8high with PD-L1+ serves as a prognostic factor for improved OS (P < 0.001) and PFS (P = 0.014). Analysis of the tumor immune microenvironment based on CD8+ TIL and PD-L1 expression is a promising independent predictor for the clinical outcome of GBC patients.