Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance

Araujo‐Castro, Marta; Pascual‐Corrales, Eider; Molina‐Cerrillo, Javier; Alonso‐Gordoa, Teresa

doi:10.3390/biomedicines9030304

Cited by 20 publications

(21 citation statements)

References 112 publications

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“…Immunotherapy provides new options for altering the routine strategies of advanced ACC, and the value of immune checkpoint inhibitor (ICI) therapy has been proposed in many studies. However, the results of a multicenter study of four ICI drugs hint at a poor overall response rate and progression-free survival in treating ACC [ 48 ]. Several pathway alterations and molecular alterations may be responsible for ICI therapy resistance, and further immunological markers of response might solve this dilemma.…”

Section: Discussionmentioning

confidence: 99%

[Retracted] Prognosis and Therapeutic Efficacy Prediction of Adrenocortical Carcinoma Based on a Necroptosis‐Associated Gene Signature

Zhong

Fan

2022

BioMed Research International

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Background. Adrenocortical carcinoma (ACC) is a rare and poor prognosis malignancy. Necroptosis is a special type of cell apoptosis, which is regulated in caspase-independent pathways and mainly induced through the activation of receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed lineage kinase domain-like pseudokinase. A precise predictive tool based on necroptosis is needed to improve the level of diagnosis and treatment. Method. Four ACC cohorts were enrolled in this study. The Cancer Genome Atlas ACC (TCGA-ACC) cohort was used as the training cohort; three datasets (GSE19750, GSE33371, and GSE49278) from Gene Expression Omnibus (GEO) platform were combined as the GEO testing cohort after removing of batch effect. Forty-nine necroptosis-associated genes were obtained from a prior study and further filtered by least absolute shrinkage and selection operator Cox regression analysis; corresponding coefficients were used to calculate the necroptosis-associated gene score (NAGs). Patients in the TCGA-ACC cohort were equally divided into two groups with the mean value of NAGs. We investigated the associations between NAGs groups and clinicopathological feature distribution and overall survival (OS) in ACC, the molecular mechanisms, and the value of NAGs in therapy prediction. A nomogram risk model was established to quantify risk stratification for ACC patients. Finally, the results were confirmed in the GEO-combined cohort. Result. Patients in the TCGA-ACC cohort were divided into high and low NAGs groups. The high NAGs group had more fatal cases and advanced stage patients than the low NAGs group ( P < 0.001 , hazard ratio HR = 13.97 , 95% confidence interval (95% CI): 4.168–46.844; survival rate: low NAGs, 7.69% vs. high NAGs, 61.53%). NAGs were validated to be negatively correlated with OS ( R = − 0.48 , P < 0.001 ) and act as an independent factor in ACC with high discriminative efficacy ( P < 0.001 , HR = 11.76 , 95% CI: 2.86–48.42). In addition, a high predictive efficacy nomogram risk model was established combining NAGs with tumor stage. Higher mutation rates were observed in the high NAGs group, and the mutation of TP53 may lead to a high T cell infiltration level among the NAGs groups. Patients belonged to the high NAGs are more sensitive to the chemotherapy of cisplatin, gemcitabine, paclitaxel, and etoposide (all P < 0.05 ). Ultimately, the same statistical algorithms were conducted in the GEO-combined cohort, and the crucial role of NAGs prediction value was further validated. Conclusion. We constructed a necroptosis-associated gene signature, revealed the prognostic value between ACC and it, systematically explored the molecular alterations among patients with different NAGs, and manifested the value of drug sensitivity prediction in ACC.

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Section: Discussionmentioning

confidence: 99%

[Retracted] Prognosis and Therapeutic Efficacy Prediction of Adrenocortical Carcinoma Based on a Necroptosis‐Associated Gene Signature

Zhong

Fan

2022

BioMed Research International

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“…Clinical response rates still lack major breakthrough success and the tumor microenvironment, which is of importance for response and resistance patterns to this kind of therapy, appears particularly complex. One key point is the impact of corticosteroid-induced immune cell depletion, causing lower numbers of circulating lymphocytes, and a high load of T-cell suppressive CD276 (B7-H3), in addition to low levels of classical biomarkers for immunotherapy including PD-L1, tumor mutational burden (TMB), TILs and MSI-H. 83 , 90 Other factors discussed as mechanisms of resistance to immunotherapy in ACC are alterations in the WNT–beta-catenin pathway that cause changes to the CD8+ population in the tumor microenvironment and alter the specific immune response. 90 Furthermore, TP53 inactivation can decrease production of cytokines necessary for immune effector cell invasion.…”

Section: Systemic Treatment – Are We Making Progress?mentioning

confidence: 99%

“…One key point is the impact of corticosteroid-induced immune cell depletion, causing lower numbers of circulating lymphocytes, and a high load of T-cell suppressive CD276 (B7-H3), in addition to low levels of classical biomarkers for immunotherapy including PD-L1, tumor mutational burden (TMB), TILs and MSI-H. 83 , 90 Other factors discussed as mechanisms of resistance to immunotherapy in ACC are alterations in the WNT–beta-catenin pathway that cause changes to the CD8+ population in the tumor microenvironment and alter the specific immune response. 90 Furthermore, TP53 inactivation can decrease production of cytokines necessary for immune effector cell invasion. However, based on the given data, immunotherapy may be applied in selected patients if available – not least due to the sobering results of chemotherapy-based salvage regimens.…”

Section: Systemic Treatment – Are We Making Progress?mentioning

confidence: 99%

Management of adrenocortical carcinoma: are we making progress?

et al. 2021

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Adrenocortical carcinoma (ACC) is a rare malignancy characterized by aggressive biology and potential endocrine activity. Surgery can offer cure for localized disease but more than half of patients relapse and primary unresectable or metastasized disease is frequent. Prognosis of metastatic ACC is still limited, with less than 15% of patients alive at 5 years. Recent advances in understanding the molecular profile of ACC underline the high complexity of this disease, which is characterized by limited drugable molecular targets as well as by a complex interplay between a yet scarcely understood microenvironment and potential endocrine activity. Particularly steroid-excess further complicates therapeutic concepts such as immunotherapy, which have markedly improved outcome in other disease entities. To date, mitotane remains the only approved drug for adjuvant and palliative care in ACC. Standard chemotherapy-based protocols with cisplatin, doxorubicin and etoposide offer only marginal improvement in long-term outcome and the number of clinical trials conducted is low due to the rarity of the disease. In the current review, we summarize principles of oncological management for ACC from localized to advanced disease and discuss novel therapeutic strategies, including targeted therapies such as tyrosine kinase inhibitors and antibodies, immunotherapy with a focus on checkpoint inhibitors, individualized treatment concepts based on molecular characterization by next generation sequencing methods, the role of theranostics and evolvement of adjuvant therapy.

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“…Therefore, it was urgently needed to analyze the relationship between ferroptosis score and immune factors in ACC. PD-1, PD-L1, and TMB were the main potential markers of response to immunotherapy in ACC [19]. Our study showed that ferroptosis scores were positively related to the expression of PD-L1 and were negatively related to the expression of TMB.…”

Section: Discussionmentioning

confidence: 48%

Ferroptosis Regulators and Tumor Microenvironment Immune Cell Infiltration Characterization in Adrenocortical Carcinoma

Shen

Liu

Liang

et al. 2022

Preprint

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Background Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and lacking effective systemic treatment options. Recent studies showed that ferroptosis play a prominent role in the initiation and development of cancer. Nonetheless, the potential roles of ferroptosis regulators in the prognosis and tumor microenvironment immunomodulator factors expression remain not fully study. Methods TCGA and GEO ACC datasets were used to investigate the relationship between ferroptosis regulators with prognosis and clinical features. Consensus clustering analysis was performed to divided ACC patients into different ferroptosis subgroups. A ferroptosis scoring system was established for individual ACC using principal component analysis algorithms. The correlation between ferroptosis score and tumor microenvironment immune cell infiltration was analyzed. Results Twenty ferroptosis regulators were differentially expressed in ACC and 17 ferroptosis regulators were closely related to the prognosis of ACC. Three ferroptosis subgroups (Cluster A, B, and C) were determined based on the expression of ferroptosis regulators. Cluster C is preferentially associated with favorable OS, PFS, upregulated antigen-presenting genes expression, and higher immune cell infiltration. GSEA also indicated that Cluster C was prominently related to immune fully activation including chemokine signaling pathway, natural killer cell-mediated cytotoxicity, T cell receptor signaling pathway, and Toll-like receptor signaling pathway. A ferroptosis scoring system was constructed and it could serve as an independent prognostic factor for ACC. The ferroptosis scores were significantly correlated with TMB, immune-checkpoint genes expression, and tumor microenvironment immune cell infiltration in ACC. Further analyses indicated that the ferroptosis score integrated with TMB, immune-checkpoint genes expression, and CD4+ T cell infiltration, could predict the prognosis of ACC. Furthermore, a nomogram was constructed to monitor the prognosis of individual ACC patient. RNA isolation and reverse transcription‑quantitative PCR (RT-qPCR) demonstrated significant differences in the expression levels of ACSL4, FANCD2 and SLC7A1 between ACC and normal tissues. Conclusion Our study demonstrated ferroptosis regulators were significantly associated with the prognosis, clinical characteristics, immune-checkpoint genes expression, and tumor microenvironment immune cell infiltration in ACC. This current study provided comprehensive evidence for further research on ferroptosis regulators in ACC and provides new enlightenment for epigenetic regulation of antitumor immune response.

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Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance

Cited by 20 publications

References 112 publications

[Retracted] Prognosis and Therapeutic Efficacy Prediction of Adrenocortical Carcinoma Based on a Necroptosis‐Associated Gene Signature

[Retracted] Prognosis and Therapeutic Efficacy Prediction of Adrenocortical Carcinoma Based on a Necroptosis‐Associated Gene Signature

Management of adrenocortical carcinoma: are we making progress?

Ferroptosis Regulators and Tumor Microenvironment Immune Cell Infiltration Characterization in Adrenocortical Carcinoma

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