Background The tumor immunological microenvironment (TIME) has a prominent impact on prognosis and immunotherapy. However, the heterogeneous TIME and the mechanisms by which TIME affects immunotherapy have not been elucidated in hepatocellular carcinoma (HCC). Methods A total of 2195 eligible HCC patients from TCGA and GEO database were collected. We comprehensively explored the different heterogeneous TIME phenotypes and its clinical significance. The potential immune escape mechanisms and what genomic alterations may drive the formation of different phenotypes were further investigated. Results We identified three phenotypes in HCC: TIME-1, the “immune-deficiency” phenotype, with immune cell depletion and proliferation; TIME-2, the “immune-suppressed” phenotype, with enrichment of immunosuppressive cells; TIME-3, the “immune-activated phenotype”, with abundant leukocytes infiltration and immune activation. The prognosis and sensitivity to both sorafenib and immunotherapy differed among the three phenotypes. We also underlined the potential immune escape mechanisms: lack of leukocytes and defective tumor antigen presentation capacity in TIME-1, increased immunosuppressive cells in TIME-2, and rich in immunoinhibitory molecules in TIME-3. The different phenotypes also demonstrated specific genomic events: TIME-1 characterized by TP53, CDKN2A, CTNNB1, AXIN1 and FOXD4 alterations; TIME-2 characterized by significant alteration patterns in the PI3K pathway; TIME-3 characterized by ARID1A mutation. Besides, the TIME index (TI) was proposed to quantify TIME infiltration pattern, and it was a superior prognostic and immunotherapy predictor. A pipeline was developed to classify single patient into one of these three subtypes and calculated the TI. Conclusions We identified three TIME phenotypes with different clinical outcomes, immune escape mechanisms and genomic alterations in HCC, which could present strategies for improving the efficacy of immunotherapy. TI as a novel prognostic and immunotherapeutic signature that could guide personalized immunotherapy and clinical management of HCC.
BackgroundA considerable number of patients with stage II/III colorectal cancer (CRC) will relapse within 5 years after surgery, which is a leading cause of death in early-stage CRC. The current TNM stage system is limited due to the heterogeneous clinical outcomes displayed in patients of same stage. Therefore, searching for a novel tool to identify patients at high recurrence-risk for improving post-operative individual management is an urgent need.MethodsUsing four independent public cohorts and qRT-PCR data from 66 tissues, we developed and validated a recurrence-associated immune signature (RAIS) based on global immune genes. The clinical and molecular features, tumor immune microenvironment landscape, and immune checkpoints profiles of RAIS were also investigated.ResultsIn five independent cohorts, this novel scoring system was proven to be an independent recurrent factor and displayed excellent discrimination and calibration in predicting the recurrence-risk at 1~5 years. Further analysis revealed that the high-risk group displayed high mutation rate of TP53, while the low-risk group had more abundance of activated CD4+/CD8+ T cells and high expression of PD-1/PD-L1.ConclusionsThe RAIS model is highly predictive of recurrence in patients with stage II/III CRC, which might serve as a powerful tool to further optimize decision-making in adjuvant chemotherapy and immunotherapy, as well as tailor surveillance protocol for individual patients.
Background A large number of patients with stage II/III colorectal cancer (CRC) have a high recurrence rate after radical resection. We aimed to develop a novel tool to stratify patients with different recurrence-risk for optimizing decision-making in post-operative surveillance and therapeutic regimens. Methods We retrospectively enrolled four independent cohorts from the Gene Expression Omnibus and 66 CRC tissues from our hospital. The initial signature discovery was conducted in GSE143985 (n = 91). This was followed by independent validation of this signature in GSE17536 (n = 111), GSE29621 (n = 40), and GSE92921 (n = 59). Further experimental validation using qRT-PCR assays (n = 66) was performed to ensure the robustness and clinical feasible of this signature. Results We developed a novel recurrence-related signature consisting of six genes. This signature was validated to be significantly associated with dismal recurrence-free survival in five cohorts GSE143985 (HR: 4.296 [2.612–7.065], P < 0.0001), GSE17536 (HR: 2.354 [1.662–3.334], P < 0.0001), GSE29621 (HR: 3.934 [1.622–9.539], P = 0.0024), GSE92921 (HR: 7.080 [2.011–24.924], P = 0.0023), and qPCR assays (HR: 3.654 [2.217–6.020], P < 0.0001). This signature was also proven to be an independent recurrent factor. More importantly, this signature displayed excellent discrimination and calibration in predicting the recurrence-risk at 1–5 years, with most AUCs were above 0.9, average C-index for the five cohorts was 0.8795, and near-perfect calibration. Conclusions We discovered and experimental validated a novel gene signature with stable and powerful performance for identifying patients at high recurrence-risk in stage II/III CRC.
Background: The tumor immunological microenvironment (TIME) has a prominent impact on prognosis and immunotherapy. However, the heterogeneous TIME and the mechanisms by which TIME affects immunotherapy have not been elucidated in hepatocellular carcinoma (HCC).Methods: A total of 2195 eligible HCC patients from TCGA and GEO database were collected. We comprehensively explored the different heterogeneous TIME phenotypes and its clinical significance. The potential immune escape mechanisms and what genomic alterations may drive the formation of different phenotypes were further investigated.Results: We identified three phenotypes in HCC: TIME-1, the “immune-deficiency” phenotype, with immune cell depletion and proliferation; TIME-2, the “immune-suppressed” phenotype, with being in immunosuppressive states; TIME-3, the “immune-activated phenotype”, with abundant leukocytes infiltration and immune activation. The prognosis and sensitivity to both sorafenib and immunotherapy differed among the three phenotypes. We also underlined the potential immune escape mechanisms: lack of leukocytes and defective tumor antigen presentation capacity in TIME-1, increased immunosuppressive cells in TIME-2, and rich in immunoinhibitory molecules in TIME-3. The different phenotypes also demonstrated specific genomic events: TIME-1 characterized by TP53, CDKN2A, CTNNB1, AXIN1 and FOXD4 alterations; TIME-2 characterized by significant alteration patterns in the PI3K pathway; TIME-3 characterized by ARID1A mutation. Besides, the TIME index (TI) was proposed to quantify TIME infiltration pattern, and it was a superior prognostic and immunotherapy predictor. A pipeline was developed to classify single patient into one of these three subtypes and calculated the TI. Conclusions: We identified three TIME phenotypes with different clinical outcomes, immune escape mechanisms and genomic alterations in HCC, which could present strategies for improving the efficacy of immunotherapy. TI as a novel prognostic and immunotherapeutic signature that could guide personalized immunotherapy and clinical management of HCC.
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