&amp;beta;-Catenin-driven adrenocortical carcinoma is characterized with immune exclusion

Liu, Shenghua; Ding, Guanxiong; Zhou, Zhongwen; Feng, Chenchen

doi:10.2147/ott.s159979

Cited by 25 publications

(20 citation statements)

References 26 publications

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“…Therefore, either overactivation of the Wnt/ β -catenin pathway or loss of p53 is potential tumor-intrinsic factors that, altering on the ability of ACC cells to recruit BAFT3 DC cell and leading to T-cell exclusion, likely indicate that this type of tumor is potentially resistant to immunotherapy. This point is strengthened by results reported on CTNNB1 expression and T-cell infiltration that have been investigated in a series of ACC tumors, showing that the increased CTNNB1 expression correlated with reduced infiltration in T cells [40]. Interestingly, high levels of CTNNB1 expression have been associated as well with increased cortisol levels [40] that likely contribute to the clinical resistance of ACC to immunotherapy [41].…”

Section: Immunologic Properties Of Accmentioning

confidence: 93%

Molecular Drivers of Potential Immunotherapy Failure in Adrenocortical Carcinoma

Fiorentini

Grisanti

Cosentini

et al. 2019

Journal of Oncology

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Adrenocortical carcinoma (ACC) is a rare, highly aggressive cancer, often insensitive to conventional chemotherapeutics agents. Early diagnosis, followed by radical surgical resection plus/minus adjuvant mitotane therapy, is nowadays the only valuable option. Unfortunately, one out of four patients has metastatic disease at diagnosis and most of radically resected ACC patients are destined to recur with local or metastatic disease. Numerous efforts aimed at identifying molecular alterations crucial for ACC pathogenesis have been extensively conducted, with the hope to develop new treatments. Indeed, multiple genes and pathways have been identified as potentially targetable in ACC patients; however, despite the strong preclinical rationale, translational findings to clinical trials led to date to disappointing results. The immunotherapeutic intervention targeting T-cell checkpoint molecules has been proposed as well, but results obtained in early studies indicate that ACC patients would be unlikely to benefit from immunotherapy. Genetic alterations of different pathways involved in ACC carcinogenesis are also known substrates of resistance to immunotherapy. Among them, β-catenin gene CTNNB1 and TP53 gene are frequently mutated in ACC samples. Overactivation of the β-catenin pathway and loss of p53 protein function are potential tumor-intrinsic factors that, impacting on the ability of ACC cells to recruit dendritic cells, leading to T-cell exclusion, put this tumor among those that are potentially resistant to immunotherapy. Moreover, the steroid phenotype, which implies glucocorticoids hypersecretion in a subset of ACC, contributes to generating an immunosuppressive microenvironment. Here, we review clinical results of immunotherapy in ACC and we highlight molecular mechanisms driving immunotherapy failure in ACC, suggesting possible approaches to overcome resistance.

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Section: Immunologic Properties Of Accmentioning

confidence: 93%

Molecular Drivers of Potential Immunotherapy Failure in Adrenocortical Carcinoma

Fiorentini

Grisanti

Cosentini

et al. 2019

Journal of Oncology

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“…As a convenient web-based resource, TIMER can also make the relationship between gene expression and tumor purity in cancer visible [27]. The gene module on TIMER estimates the correlation between gene expression and tumor-infiltrating immune cells (TIICs) [28]. Based on TIMER, we analyzed the relationship between STAT3 expression and tumor purity in diverse cancer types.…”

Section: Timer Databasementioning

confidence: 99%

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

et al. 2020

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Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and regulates tumorigenesis. However, the functions of STAT3 in immune and drug response in cancer remain elusive. Hence, we aim to reveal the impact of STAT3 in immune infiltration and drug response comprehensively by bioinformatics analysis. The expression of STAT3 and its relationship with tumor stage were explored by Tumor Immune Estimation Resource (TIMER), Human Protein Altas (HPA), and UALCAN databases. The correlations between STAT3 and immune infiltration, gene markers of immune cells were analyzed by TIMER. Moreover, the association between STAT3 and drug response was evaluated by the Cancer Cell Line Encyclopedia (CCLE) and Cancer Therapeutics Response Portal (CTRP). The results suggested that the mRNA transcriptional level of STAT3 was lower in tumors than normal tissues and mostly unrelated to tumor stage. Besides, the protein expression of STAT3 decreased in colorectal and renal cancer compared with normal tissues. Importantly, STAT3 was correlated with immune infiltration and particularly regulated tumor-associated macrophage (TAM), M2 macrophage, T-helper 1 (Th1), follicular helper T (Treg), and exhausted T-cells. Remarkably, STAT3 was closely correlated with the response to specified inhibitors and natural compounds in cancer. Furthermore, the association between STAT3 and drug response was highly cell line type dependent. Significantly, the study provides thorough insight that STAT3 is associated with immunosuppression, as well as drug response in clinical treatment.

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“…In the tumor microenvironment, the immunosuppressive and immunostimulating signatures have a potential prognostic value for some cancer types [9,10]. Recently, Liu et al reported that CD8 + T cells and expression of programmed death ligand 1 (PD-L1/B7-H1) were significantly associated with improved survival, indicating a potential role for the immune signature in the assessment of ACC prognosis [11]. However, PD-L1 is reportedly only expressed in approximately 10% of ACC tumor cells and cell membranes [12,13].…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological and Prognostic Characteristics of CD276 (B7-H3) Expression in Adrenocortical Carcinoma

et al. 2020

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Background. Adrenocortical carcinoma (ACC) is a rare malignant endocrine tumor with a high tumor recurrence rate and poor postoperative survival. Recent studies suggest that CD276- (B7-H3) targeted therapy represents a promising therapeutic option for solid tumors. However, little is known about the expression status of CD276 or its association with progression and prognosis of ACC. Methods. Clinical data were retrospectively analyzed from patients who underwent resection of ACC at our institution (n=48). Archived, formalin-fixed, and paraffin-embedded samples were collected for immunohistochemical analysis, and the correlation between CD276 expression and clinicopathological parameters was evaluated. Kaplan–Meier and univariate/multivariate Cox regression methods were implemented to identify any prognostic effects. Data from The Cancer Genome Atlas (TCGA) ACC cohort (n=77) were retrieved for quantitative validation analysis. Results. Positive expression of CD276 was detected on the cell membrane and in the cytoplasm of cancer cells or tumor-associated vascular cells in 91.67% (44/48) of ACCs. Vascular expression of CD276 was associated with local aggression (higher T stage, P=0.029) and advanced ENSAT stage (P=0.02). Specifically, patients with a higher CD276-positive cancer cell density exhibited significantly worse overall survival and recurrence-free survival in our cohort (HR=2.8, P=0.01, and HR=7.52, P<0.001, respectively) and in the validation cohort (HR=2.4, P=0.033, and HR=3.7, P<0.001, respectively). The prognostic association remained significant in multivariate Cox regression analysis. Further analysis indicated that CD276 participates in regulating the immune response as well as in the malignant biological behaviors of ACC. Conclusion. These findings highlight the immune checkpoint factor CD276 as an independent prognostic factor and a potential therapeutic target in ACC.

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β-Catenin-driven adrenocortical carcinoma is characterized with immune exclusion

Cited by 25 publications

References 26 publications

Molecular Drivers of Potential Immunotherapy Failure in Adrenocortical Carcinoma

Molecular Drivers of Potential Immunotherapy Failure in Adrenocortical Carcinoma

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

Clinicopathological and Prognostic Characteristics of CD276 (B7-H3) Expression in Adrenocortical Carcinoma

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