Melanoma Metastases to the Adrenal Gland Are Highly Resistant to Immune Checkpoint Inhibitors

Abstract

Background: Adrenal gland metastases (AGMs) are common in advanced-stage melanoma, occurring in up to 50% of patients. The introduction of immune checkpoint inhibitors (ICIs) has markedly altered the outcome of patients with melanoma. However, despite significant successes, anecdotal evidence has suggested that treatment responses in AGMs are significantly lower than in other metastatic sites. We sought to investigate whether having an AGM is associated with altered outcomes and whether ICI responses are dampened in the adrenal glands. Patients and Methods: We retrospectively compared ICI responses and overall survival (OS) in 68 patients with melanoma who were diagnosed with an AGM and a control group of 100 patients without AGMs at a single institution. Response was determined using RECIST 1.1. OS was calculated from time of ICI initiation, anti–PD-1 initiation, initial melanoma diagnosis, and stage IV disease diagnosis. Tumor-infiltrating immune cells were characterized in 9 resected AGMs using immunohistochemical analysis. Results: Response rates of AGMs were significantly lower compared with other metastatic sites in patients with AGMs (16% vs 22%) and compared with those without AGMs (55%). Patients with AGMs also had significantly lower median OS compared with those without AGMs (3.1 years vs not reached, respectively). We further observed that despite this, AGMs exhibited high levels of tumor-infiltrating immune cells. Conclusions: In this cohort of patients with melanoma, those diagnosed with an AGM had lower ICI response rates and OS. These results suggest that tissue-specific microenvironments of AGMs present unique challenges that may require novel, adrenal gland–directed therapies or surgical resection.

Metastasis of Melanoma to the Adrenal Glands: A Case Report and Literature Review

“…Although ICIs have revolutionized the treatment of melanoma, adrenal gland metastases from melanoma are unique in that they remain highly resistant to these new treatments [ 2 , 3 ]. Consequently, patients with metastatic melanoma who have adrenal gland metastases have lower overall survival than those without adrenal gland metastases [ 2 ].…”

“…Although ICIs have revolutionized the treatment of melanoma, adrenal gland metastases from melanoma are unique in that they remain highly resistant to these new treatments [ 2 , 3 ]. Consequently, patients with metastatic melanoma who have adrenal gland metastases have lower overall survival than those without adrenal gland metastases [ 2 ]. It is hypothesized that the reason the adrenal gland is a sanctuary site for metastases is that corticosteroid production creates an immunosuppressive tumor microenvironment.…”

“…It is hypothesized that the reason the adrenal gland is a sanctuary site for metastases is that corticosteroid production creates an immunosuppressive tumor microenvironment. Corticosteroids suppress lymphocyte function and upregulate beta-catenin, which promotes immune cell exclusion from the tumor microenvironment [ 2 ]. Furthermore, corticosteroids slow dendritic cell maturation and limit the ability of T cells to recognize tumor cells, which allows tumor cells to evade checkpoint inhibition and proliferate [ 2 ].…”

“…Corticosteroids suppress lymphocyte function and upregulate beta-catenin, which promotes immune cell exclusion from the tumor microenvironment [ 2 ]. Furthermore, corticosteroids slow dendritic cell maturation and limit the ability of T cells to recognize tumor cells, which allows tumor cells to evade checkpoint inhibition and proliferate [ 2 ]. Other molecules produced in the adrenal gland, such as sex hormones and catecholamines, further suppress the immune system [ 2 ].…”

“…The prognosis of metastatic melanoma has improved considerably in recent years with the use of targeted therapeutic agents, particularly immune checkpoint inhibitors (ICIs) [ 1 ]. Despite the new advances in treatment, adrenal metastases from melanoma are unique in that they remain highly resistant to ICIs [ 2 , 3 ]. The true incidence of adrenal involvement from primary cutaneous melanoma is unknown, and little data exists regarding the natural history of patients with this condition [ 4 ].…”