Molecular Drivers of Potential Immunotherapy Failure in Adrenocortical Carcinoma

Abstract

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.

Identification of prognostic genes in adrenocortical carcinoma microenvironment based on bioinformatic methods

“…Adrenal tumors are very common, approximately 3%‐10% of the human population suffers from the disease, and most of them are nonfunctional adrenocortical adenomas (benign lesions) . However, adrenocortical carcinoma (ACC) is extremely rare with an incidence of 0.7‐2 cases per million people annually . Surgery is the first‐line therapy for patients with localized ACC (stage I, II diseases and most of stage III diseases), while different therapy methods (molecularly targeted therapy, immunotherapy, adjuvant therapy, and so on) or multidisciplinary approaches are applied in advanced patients in order to achieve improvement in the prognosis .…”

PDL1 expression is associated with longer postoperative, survival in adrenocortical carcinoma

“…Possible mechanisms of ACC resistance to PD1/PDL1 inhibitors have been suggested, such as WNT-β-catenin amplification, TP53 mutation, abnormal PD-L1 expression and increased production of steroids. 32,33 PDL1 expression has been studied in many cancers, with evidence of correlations with clinicopathological features, including survival, in several studies. [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] In ACC, only one study analyzed the prevalence and prognostic value of PDL1 expression 49 in a small series of 28 samples and at the protein level using immunohistochemistry (IHC).…”

Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells

“…Finally, our data on the inhibitory effect of trabectedin on Wnt/β-catenin are interesting due to the major role of this pathway in proliferation and resistance to antineoplastic agents of ACC cells [21,22,48].…”

“…The Wnt/β-catenin pathway activation in ACC is notoriously a major tumor driver in the pathogenesis of ACC [20] and a mechanism of ACC resistance to modern immunotherapy [21,22]. NCI-H295R cells harbor an activating point mutation in the β-catenin gene CTNNB1 that modifies the Ser45 of exon 3, leading to enhanced Wnt/β-catenin transcriptional activity and increased nuclear localization [23,24].…”