The Immunotherapy Landscape in Adrenocortical Cancer.
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ABSTRACT:
SUBMITTER: Pegna GJ
PROVIDER: S-EPMC8199088 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Paediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyse 37 adrenocortical tumours (ACTs) by whole-genome, whole-exome and/or transcriptome sequencing. Most cases (91%) show loss of heterozygosity (LOH) of chromosome 11p, with uniform selection against the maternal chromosome. IGF2 on chromosome 11p is overexpressed in 100% of the tumours. TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 are observed in 28 ACTs (76%). Chromosomes 11p and 17 undergo copy-neutral LOH early during tumorigenesis, suggesting tumour-driver events. Additional genetic alterations include recurrent somatic mutations in ATRX and CTNNB1 and integration of human herpesvirus-6 in chromosome 11p. A dismal outcome is predicted by concomitant TP53 and ATRX mutations and associated genomic abnormalities, including massive structural variations and frequent background mutations. Collectively, these findings demonstrate the nature, timing and potential prognostic significance of key genetic alterations in paediatric ACT and outline a hypothetical model of paediatric adrenocortical tumorigenesis.
| S-EPMC4352712 | biostudies-literature
Project description:BackgroundAdrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14-17 month median overall survival. We asked whether tumors from patients with advanced or metastatic ACC would offer clues as to putative genes that might have critical roles in disease progression or in more aggressive disease biology.MethodsWe conducted comprehensive genomic and expression analyses of ACCs from 43 patients, 30 female, and 42 from metastatic sites, including deep sequencing, copy number analysis, mRNA expression and microRNA arrays.ResultsCopy number gains and losses were similar to that previously reported for ACC. We identified a median mutation rate of 3.38 per megabase (Mb). The mutational signature was characterized by a predominance of C > T, C > A and T > C transitions. Only cancer genes TP53 (26%) and beta-catenin (CTNNB1, 14%) were mutated in more than 10% of samples. The TCGA-identified putative cancer genes MEN1 and PRKAR1A were found in low frequency-4.7 and 2.3%, respectively. The majority of the mutations were in genes not implicated in the etiology or maintenance of cancer. Specifically, amongst the 38 genes that were mutated in more than 9% of samples, only four were represented in Tier 1 of the 576 COSMIC Cancer Gene Census (CCGC). Thus, 82% of genes found to have mutations likely have no role in the etiology or biology of ACC; while the role of the other 18%, if any, remains to be proven. Finally, the transcript length for the 38 most frequently mutated genes in ACC is statistically longer than the average of all coding genes, raising the question of whether transcript length in part determined mutation probability.ConclusionsWe conclude that the mutational and expression profiles of advanced and metastatic tumors are very similar to those from newly diagnosed patients-with very little in the way of genomic aberration to explain differences in biology. With relatively low mutation rates, few major oncogenic drivers, and loss of function mutations in several epigenetic regulators, an epigenetic basis for ACC may be postulated and serve as the basis for future studies.
| S-EPMC7640690 | biostudies-literature
Project description:Penile cancer is a rare malignancy and usually refers to penile squamous cell carcinoma (PSCC), which accounts for more than 95% of all penile malignancies. Although organ-sparing surgery is an effective treatment for early-stage PSCC, surgical intervention alone is often not curative for advanced PSCC with metastases to the inguinal and/or pelvic lymph nodes; thus, systemic therapy is required (usually platinum-based chemotherapy and surgery combined). However, chemotherapy for PSCC has proven to be of limited efficacy and is often accompanied by high toxicity, and patients with advanced PSCC usually have poor prognosis. The limited treatment options and poor prognosis indicate the unmet need for advanced PSCC. Immune-based therapies have been approved for a variety of genitourinary and squamous cell carcinomas but are rarely reported in PSCC. To date, several studies have reported high expression of PDL1 in PSCC, supporting the potential application of immune checkpoint inhibitors in PSCC. In addition, human papillomavirus (HPV) infection is highly prevalent in PSCC and plays a key role in the carcinogenesis of HPV-positive PSCC, suggesting that therapeutic HPV vaccine may also be a potential treatment modality. Moreover, adoptive T cell therapy (ATC) has also shown efficacy in treating advanced penile cancer in some early clinical trials. The development of new therapeutics relies on understanding the underlying biological mechanisms and processes of tumor initiation, progression and metastasis. Therefore, based on the interest, we reviewed the tumor immune microenvironment and the emerging immunotherapy for penile cancer.
| S-EPMC9745054 | biostudies-literature
Project description:BackgroundCancer stem cells (CSCs) have been proven to influence drug resistance, recurrence, and metastasis in tumors. Our study aimed to identify stemness-related prognostic biomarkers for new therapeutic strategies in adrenocortical carcinoma.MethodsRNA-seq data and clinical characteristics were downloaded from The Cancer Genome Atlas (TCGA). The stemness indexes, mDNAsi and mRNAsi, were calculated to classify all samples into low-score and high-score groups. Two algorithms, based on the R language, ESTIMATE and single-sample Gene Set Enrichment Analysis (ssGSEA) were used to assess the immune cell infiltration states of adrenocortical carcinoma patients. Weighted Gene Co-expression Network Analysis (WGCNA) was used to find genes that were related to the stemness of cancer. By bioinformatics methods, the correlations between biomarkers capable of predicting immune checkpoint inhibitors (ICIs) responses and stemness of cancer were explored.ResultsHigh-mRNAsi predicted shorter overall survival (OS) and a higher metastatic trend in adrenocortical carcinoma (ACC) patients. Compared with the low-mRNAsi group, the high-mRNAsi group had a lower ImmuneScore and StromalScroe. Twenty-two stemness-related prognostic genes were obtained by WGCNA, which focused on the function of the cell cycle and cell mitosis. Immune cell infiltration, especially CD8+T cell, increased in the low-mRNAsi group compared with the high-mRNAsi group. Lower expression of PD-L1, CTLA-4, and TIGHT was evaluated in the high-mRNAsi group.ConclusionsACC patients with high-mRNAsi have poor prognosis and less immune cell infiltration. Combined with the finding of lower expression of CTLA-4, TIGHT, and PD-L1 in the high-mRNAsi group, we came to the conclusion that stemness index is a potential biomarker to predict the effectiveness of ICIs.
| S-EPMC8334864 | biostudies-literature
Project description:ImportanceThere is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing at the time of this narrative review. The objective of this review is to describe the current status of immunotherapy in breast cancer, highlighting its potential in both early-stage and metastatic disease.ObservationsAfter searching ClinicalTrials.gov on April 24, 2018, and PubMed up to June 30, 2018, to identify breast cancer immunotherapy trials, we found that immune checkpoint blockade (ICB) is the most investigated form of immunotherapy in breast cancer. Use of ICB as monotherapy has achieved objective responses in patients with breast cancer, with higher rates seen when administered in earlier lines of therapy. For responding patients, those responses are durable. More recent data suggest clinical efficacy when ICB is given in combination with chemotherapy. Ongoing studies are evaluating combination strategies pairing ICB with additional chemotherapeutic agents, targeted therapy, vaccines, and local ablative therapies to enhance response. To date, robust predictive biomarkers for response to ICB have not been established.Conclusions and relevanceIt is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions. Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors.
| S-EPMC8452050 | biostudies-literature
Project description:BackgroundCancer immunotherapy with immune checkpoint blockade (CKB) is now standard of care for multiple cancers. The clinical response to CKB is associated with T cell immunity targeting cancer-induced mutations that generate novel HLA-binding epitopes (neoepitopes).MethodsHere, we developed a rapid bioinformatics pipeline and filtering strategy, EpitopeHunter, to identify and prioritize clinically relevant neoepitopes from the landscape of somatic mutations. We used the pipeline to determine the frequency of neoepitopes from the TCGA dataset of invasive breast cancers. We predicted HLA class I-binding neoepitopes for 870 breast cancer samples and filtered the neoepitopes based on tumor transcript abundance.ResultsWe found that the total mutational burden (TMB) was highest for triple-negative breast cancer, TNBC, (median = 63 mutations, range: 2-765); followed by HER-2(+) (median = 39 mutations, range: 1-1206); and lowest for ER/PR(+)HER-2(-) (median = 32 mutations, range: 1-2860). 40% of the nonsynonymous mutations led to the generation of predicted neoepitopes. The neoepitope load (NEL) is highly correlated with the mutational burden (R2 = 0.86).ConclusionsOnly half (51%) of the predicted neoepitopes are expressed at the RNA level (FPKM≥2), indicating the importance of assessing whether neoepitopes are transcribed. However, of all patients, 93% have at least one expressed predicted neoepitope, indicating that most breast cancer patients have the potential for neo-epitope targeted immunotherapy.
| S-EPMC6399957 | biostudies-literature
Project description:Immunotherapy represents a promising strategy for the treatment of cancer, which functions via the reprogramming and activation of antitumor immunity. However, adverse events resulting from immunotherapy that are related to the low specificity of tumor cell-targeting represent a limitation of immunotherapy's efficacy. The potential of nanotechnologies is represented by the possibilities of immunotherapeutical agents being carried by nanoparticles with various material types, shapes, sizes, coated ligands, associated loading methods, hydrophilicities, elasticities, and biocompatibilities. In this review, the principal types of nanovectors (nanopharmaceutics and bioinspired nanoparticles) are summarized along with the shortcomings in nanoparticle delivery and the main factors that modulate efficacy (the EPR effect, protein coronas, and microbiota). The mechanisms by which nanovectors can target cancer cells, the tumor immune microenvironment (TIME), and the peripheral immune system are also presented. A possible mathematical model for the cellular communication mechanisms related to exosomes as nanocarriers is proposed.
| S-EPMC8875018 | biostudies-literature
Project description:Despite advances in treatment strategies and surgical approaches in recent years, improving survival outcomes in esophagogastric cancer (EGC) patients treated with curative intent remains a significant area of unmet need. The recent emergence of adjuvant immunotherapy as the standard of care for resected EGC demonstrates the impact of immunotherapy in improving recurrence-free survival. Neoadjuvant and perioperative immunotherapies represent another promising approach with potential advantages over adjuvant therapy. Despite the promising results of early neoadjuvant immunotherapy studies, there are several challenges and future research needs. The optimal timing, duration and number of doses in relation to surgery and the optimal combination of immunotherapies are still unclear. In addition, rigorous correlative studies need to be performed to identify biomarkers for patient selection and treatment response prediction to maximize the benefits of neoadjuvant immunotherapy. In this review, we provide a concise summary of the current standard of care for resectable EGC and discuss the rationale for the use of immune checkpoint inhibitors in this setting and the pre-clinical and early clinical data of these novel therapies. Finally, we will examine the potential role and future direction of immunotherapy in the treatment paradigm and the perceived challenges and opportunities that lay ahead.
| S-EPMC10814157 | biostudies-literature
Project description: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.
| S-EPMC8069982 | biostudies-literature
Project description: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.
| S-EPMC6463568 | biostudies-literature