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Tumor Microenvironment in Adrenocortical Carcinoma: Barrier to Immunotherapy Success?

ABSTRACT: Adrenocortical carcinoma is a rare malignancy with aggressive behavior, with up to 40% of patients presenting with metastases at the time of diagnosis. Both conventional chemotherapeutic regimens and novel immunotherapeutic agents, many of which are currently being tested in ongoing clinical trials, have yielded modest results so far, bringing the need for a deeper understanding of adrenal cancer behavior to the forefront. In the recent years, the tumor microenvironment has emerged as a major determinant of cancer response to immunotherapy and an increasing number of studies on other solid tumors have focused on manipulating the microenvironment in the favor of the host and discovering new potential target molecules. In the present review we aim to explore the characteristics of adrenocortical cancer's microenvironment, highlighting the mechanisms of immune evasion responsible for the modest immunotherapeutic results, and identify novel potential strategies.

SUBMITTER: Georgantzoglou N

PROVIDER: S-EPMC8069982 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Tumor Microenvironment in Adrenocortical Carcinoma: Barrier to Immunotherapy Success?

Georgantzoglou Natalia N Kokkali Stefania S Tsourouflis Gerasimos G Theocharis Stamatios S

Cancers 20210409 8

Adrenocortical carcinoma is a rare malignancy with aggressive behavior, with up to 40% of patients presenting with metastases at the time of diagnosis. Both conventional chemotherapeutic regimens and novel immunotherapeutic agents, many of which are currently being tested in ongoing clinical trials, have yielded modest results so far, bringing the need for a deeper understanding of adrenal cancer behavior to the forefront. In the recent years, the tumor microenvironment has emerged as a major de ...[more]

PMID: 33918733

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Project description:BackgroundImmunotherapeutic response failure of adrenocortical carcinomas highlights a need for novel strategies targeting immune cell populations in the tumor microenvironment to overcome tumor resistance and enhance therapeutic response. A recent study explored a new link between tumor mast cell infiltration and improved outcomes in patients with adrenocortical carcinomas. We further dissect the role of mast cells in the tumor microenvironment of adrenocortical carcinomas by examining the tumor mast cell expression signatures and mast cell activity within the tumor microenvironment to provide additional insight into potential novel immunotherapeutic targets.MethodsUsing the CIBERSORTx computational immunogenomic deconvolution algorithm to analyze adrenocortical carcinoma tumor gene messenger RNA expression data (The Cancer Genome Atlas, N = 79), we estimated the abundance of tumor immune infiltrating mast cells and assessed prognostic potential of mast cell signaling genes as pro or antitumor signatures, as well as examined the impact on overall and disease-free survival.ResultsWe stratified mast cell signaling genes with survival prognostic values (overall survival, disease-free survival, P < .05) into antitumor (ALOX5, CCL2, CCL5, CXCL10, HDC, IL16, TNF, TPSAB1, VEGFD) and protumor (CXCL1, CXCL3, CXCL8, IL4, IL13, PTGS3, TNSF4, VEGFD) groups. Antitumor mast cell signature, as the predominant phenotype, was associated with improved overall and disease-free survival.ConclusionThe deconvolution analysis of The Cancer Genome Atlas data identified mast cell infiltration in the adrenocortical carcinoma microenvironment as predominantly associated with antitumor activity. Future studies stemming from our findings may help define the role of mast cells in the tumor microenvironment and the impact on patient survival in patients with adrenocortical carcinomas. Modulation of tumor mast cell infiltration may serve as a potential target for novel synergistic immunotherapies for the treatment and improved survival of patients with adrenocortical carcinomas.

Project description:Background: Adrenocortical carcinoma (ACC) is a rare malignant endocrine tumor derived from the adrenal cortex. Because of its highly aggressive nature, the prognosis of patients with adrenocortical carcinoma is not impressive. Hypoxia exists in the vast majority of solid tumors and contributes to invasion, metastasis, and drug resistance. This study aimed to reveal the role of hypoxia in Adrenocortical carcinoma and develop a hypoxia risk score (HRS) for Adrenocortical carcinoma prognostic prediction. Methods: Hypoxia-related genes were obtained from the Molecular Signatures Database. The training cohorts of patients with adrenocortical carcinoma were downloaded from The Cancer Genome Atlas, while another three validation cohorts with comprehensive survival data were collected from the Gene Expression Omnibus. In addition, we constructed a hypoxia classifier using a random survival forest model. Moreover, we explored the relationship between the hypoxia risk score and immunophenotype in adrenocortical carcinoma to evaluate the efficacy of immune check inhibitors (ICI) therapy and prognosis of patients. Results: HRS and tumor stage were identified as independent prognostic factors. HRS was negatively correlated with immune cycle activity, immune cell infiltration, and the T cell inflammatory score. Therefore, we considered the low hypoxia risk score group as the inflammatory immunophenotype, whereas the high HRS group was a non-inflammatory immunophenotype. In addition, the HRS was negatively related to the expression of common immune checkpoint molecules such as PD-L1, CD200, CTLA-4, and TIGIT, suggesting that patients with a lower hypoxia risk score respond better to immunotherapy. Conclusion: We developed and validated a novel hypoxia risk score to predict the immunophenotype and response of patients with adrenocortical carcinoma to immune check inhibitors therapy. These findings not only provide fresh prognostic indicators for adrenocortical carcinoma but also offer several promising treatment targets for this disease.

Project description:BackgroundCD74 is ectopically expressed in many tumors and can regulate tumor immunity. However, there are many gaps in the study of the prognostic value of CD74 expression and immune infiltration in hepatocellular carcinoma (HCC).MethodsAn online tumor database was searched to obtain data on gene/protein expression. Immune infiltration analysis was performed using the Tumor Immune Estimation Resource and Comprehensive Analysis on Multi-Omics of Immunotherapy in Pan-cancer databases. Single-cell data were obtained from the Tissue-specific Gene Expression and Regulation, Single-cell Transcriptomes of Tumor Immune Microenvironment and Tumor Immune Single-cell Hub 2 databases.ResultsCD74 was highly expressed in HCC patients. HCC patients with high CD74 expression who consumed alcohol or were negative for hepatitis virus had a better prognosis than patients with low CD74 expression. CD74 was mainly enriched in immune response regulation pathways. Both copy number variations in CD74 and CD74 expression patterns affected the infiltration levels of immune cells. Interestingly, CD74 regulated the differentiation of myeloid cells. CD74 in macrophages and dendritic cells (DCs) forms complex networks with malignant cells and hepatic progenitor cell (HPC)-like cells, respectively. High CD74 expression in HPC-like cells and malignant cells significantly decreased the fraction of C-type lectin domain family 9 A (CLEC9A)-cDC1+ DCs and IL-1B+ macrophages, respectively. Their crosstalk subsequently shaped the tumor microenvironment of HCC, possibly through the CD74-MIF axis. Importantly, patients with high CD74 expression presented higher immune scores and achieved good outcomes after receiving immunotherapy.ConclusionHigh CD74 expression is associated with the abundance of a variety of immune cell types, mediating interactions among tumor and immune cells and shaping the malignant behavior of HCC. In summary, CD74 may be a hallmark for determining the prognosis and immune cell infiltration levels of HCC patients.

Dataset Information

Tumor Microenvironment in Adrenocortical Carcinoma: Barrier to Immunotherapy Success?

Publications

Tumor Microenvironment in Adrenocortical Carcinoma: Barrier to Immunotherapy Success?

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