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TGFβ signaling activation correlates with immune-inflamed tumor microenvironment across human cancers and predicts response to immunotherapy.

ABSTRACT: Considering the determining role of TGFβ signaling in the tumor microenvironment (TME) on immune evasion, the inhibition of signaling is expected to enhance the therapeutic efficacy of immunotherapies, especially immune checkpoint blockade (ICB), which is confirmed in preclinical data. However, successive failures in clinical translation occur at the initial stage. To provide a better understanding of TGFβ signaling within the TME and its relation to the individual immunological status, we performed a pan-cancer analysis comparing the activation of TGFβ pathway among different TMEs based on multi-omics data. Compared with non-inflamed tumors, increased TGFβ signaling activity appeared in four non-cancer cell types within TME in inflamed tumors. Significant correlations were revealed between TGFβ signaling and reliable biomarkers for ICB therapy, as well as between TGFβ signaling and HPV status. Our findings contribute to explain the inconsistency between preclinical and clinical research, and are crucial to optimizing upcoming clinical trial design and improving patient stratification for personalized prediction.

SUBMITTER: Xia J

PROVIDER: S-EPMC9769449 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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TGFβ signaling activation correlates with immune-inflamed tumor microenvironment across human cancers and predicts response to immunotherapy.

Xia Jiadong J Zhang Qijie Q Luan Jiaochen J Min Pengxiang P Zhang Hanjie H Chen Gang G Ji Chengjian C Song Ninghong N

Cell cycle (Georgetown, Tex.) 20220803 1

Considering the determining role of TGFβ signaling in the tumor microenvironment (TME) on immune evasion, the inhibition of signaling is expected to enhance the therapeutic efficacy of immunotherapies, especially immune checkpoint blockade (ICB), which is confirmed in preclinical data. However, successive failures in clinical translation occur at the initial stage. To provide a better understanding of TGFβ signaling within the TME and its relation to the individual immunological status, we perfo ...[more]

PMID: 35923142

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Project description:BackgroundGlioma is an aggressive tumor of the central nervous system. Caspase-6 (CASP6) plays a crucial role in cell pyroptosis and is a central protein involved in many cellular signaling pathways. However, the association between CASP6 and prognosis of glioma patients remains unclear.MethodsFour bioinformatic databases were analyzed to identify differentially expressed genes (DEGs) between glioma and healthy tissues. Eighty-one protein-coding pyroptosis-related genes (PRGs) were obtained from the GeneCards database. The pyroptosis-related DEGs (PRDEGs) were extracted from each dataset, and CASP6 was found to be aberrantly expressed in glioma. We then investigated the biological functions of CASP6 and the relationship between CASP6 expression and the tumor microenvironment and immunocyte infiltration. The half maximal inhibitory concentration of temozolomide and the response to immune checkpoint blockade in the high- and low-CASP6 expression groups were estimated using relevant bioinformatic algorithms. Quantitative real-time reverse transcription PCR and western blotting were carried out to confirm the different expression levels of CASP6 between human astrocytes and glioma cell lines (U251 and T98G). We determined the role of CASP6 in the tumorigenesis of glioma by knocking down CASP6 in U251 and T98G cell lines.ResultsWe found that CASP6 was overexpressed in glioma samples and in glioma cell lines. CASP6 expression in patients with glioma correlated negatively with overall survival. In addition, CASP6 expression correlated positively with the degree of glioma progression. Functional analysis indicated that CASP6 was primarily involved in the immune response and antigen processing and presentation. Patients with high CASP6 levels responded more favorably to temozolomide, while patients with low expression of CASP6 had a better response to immunotherapy. Finally, in vitro experiments showed that CASP6 knockdown inhibited glioma proliferation.ConclusionsThe pyroptosis-related gene CASP6 might represent a sensitive prognostic marker for patients with glioma and might predict their response of immunotherapy and temozolomide therapy. Our results might lead to more precise immunotherapeutic strategies for patients with glioma.

Project description:IntroductionMethylenetetrahydrofolate dehydrogenase 2 (MTHFD2), whose aberrant expression is common in cancers, has recently been identified as a potential regulator of immune response. However, its immune-related role in bladder cancer (BLCA) and its association with immunotherapy efficacy remain unclear.MethodsRNA sequencing data from The Cancer Genome Atlas (TCGA) was applied to analyze the immunological roles and prognostic value of MTHFD2 in pan-cancers. The association of MTHFD2 with several immunological features of tumor microenvironment (TME), including cancer-immunity cycle, immune cells infiltration, immune checkpoints expression, and T cell inflamed score was analyzed in TCGA-BLCA cohort. The predictors of cancer treatments effectiveness, including the expression and mutation of certain genes, molecular subtypes, and several signatures were evaluated as well. These results were validated by another independent cohort (GSE48075). Finally, the predictive value of MTHFD2 for TME and immunotherapy efficacy were validated using immunohistochemistry assay and RNA sequencing data from IMvigor210 cohort, respectively.ResultsMTHFD2 was found to be positively associated with several immunological features of an inflamed tumor microenvironment (TME) in various cancers and could predict BLCA patients' prognosis. In BLCA, high expression of MTHFD2 was observed to be positively related with the cancer-immunity cycle, the infiltration of several immune cells, and the expression of immunoregulators and T-cell inflamed scores, indicating a positive correlation with the inflamed TME. Moreover, patients with high MTHFD2 expression were more likely to be basal-like subtypes and respond to BLCA treatments, including immunotherapy, chemotherapy, and target therapy. The clinical data of the IMvigor210 cohort confirmed the higher response rates and better survival benefits of immunotherapy in high-MTHFD2-expression patients.ConclusionCollectively, high MTHFD2 predicts an inflamed TME, a basal-like subtype, and a better response to various therapeutic strategies, especially the ICB therapy, in bladder cancer.

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Project description:Background: Gastric carcinoma (GC) is a carcinoma with a high incidence rate, and it is a deadly carcinoma globally. An effective tool, that is, able to predict different survival outcomes for GC patients receiving individualized treatments is deeply needed. Methods: In total, data from 975 GC patients were collected from TCGA-STAD, GSE15459, and GSE84437. Then, we performed a comprehensive unsupervised clustering analysis based on 54 TGFβ-pathway-related genes and correlated these patterns with tumor microenvironment (TME) cell-infiltrating characteristics. WGCNA was then applied to find the module that had the closest relation with these patterns. The least absolute shrinkage and selection operator (LASSO) algorithm was combined with cross validation to narrow down variables and random survival forest (RSF) was used to create a risk score. Results: We identified two different TGFβ regulation patterns and named them as TGFβ Cluster 1 and Cluster 2. TGFβ Cluster 1 was linked to significantly poorer survival outcomes and represented an inflamed TME subtype of GC. Using WGCNA, a module (magenta) with the closest association with the TGFβ clusters was identified. After narrowing down the gene list by univariate Cox regression analysis, the LASSO algorithm and cross validation, four of the 243 genes in the magenta module were applied to build a risk score. The group with a higher risk score exhibited a considerably poorer survival outcome with high predictive accuracy. The risk score remained an independent risk factor in multivariate Cox analysis. Moreover, we validated this risk score using GSE15459 and GSE84437. Furthermore, we found that the group with a higher risk score represented an inflamed TME according to the evidence that the risk score was remarkably correlated with several steps of cancer immunity cycles and a majority of the infiltrating immune cells. Consistently, the risk score was significantly related to immune checkpoint genes and T cell-inflamed gene expression profiles (GEPs), indicating the value of predicting immunotherapy. Conclusions: We have developed and validated a TGFβ-associated signature, that is, capable of predicting the survival outcome as well as depicting the TME immune characteristics of GC. In summary, this signature may contribute to precision medicine for GC.

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TGFβ signaling activation correlates with immune-inflamed tumor microenvironment across human cancers and predicts response to immunotherapy.

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TGFβ signaling activation correlates with immune-inflamed tumor microenvironment across human cancers and predicts response to immunotherapy.

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