Adrenal tumors provide insight into the role of cortisol in NK cell activity

in Endocrine-Related Cancer
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  • 1 Corcept Therapeutics, Menlo Park, California, USA
  • | 2 Department of Endocrine Neoplasia and Hormonal Disorders, MD Anderson Cancer Center, Houston, Texas, USA

Correspondence should be addressed to A E Greenstein: agreenstein@corcept.com
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Elevated glucocorticoid (GC) activity may limit tumor immune response and immune checkpoint inhibitor (ICI) efficacy. Adrenocortical carcinoma (ACC) provides a unique test case to assess correlates of GC activity, as approximately half of ACC patients exhibit excess GC production (GC+). ACC multi-omics were analyzed to identify molecular consequences of GC+ and assess the rationale for combining the glucocorticoid receptor (GR) antagonist relacorilant with an ICI. GC status, mRNA expression, and DNA mutation and methylation data from 71 adrenal tumors were accessed via The Cancer Genome Atlas. Expression of 858 genes differed significantly between GC− and GC+ ACC cases. KEGG pathway analysis showed higher gene expression of three pathways involved in steroid synthesis and secretion in GC+ cases. Fifteen pathways, most related to NK cells and other immune activity, showed lower expression. Hypomethylation was primarily observed in the steroid synthesis pathways. Tumor-infiltrating CD4+ memory (P = 0.003), CD8+ memory (P < 0.001), and NKT-cells (P = 0.014) were depleted in GC+ cases; tumor-associated neutrophils were enriched (P < 0.001). Given the pronounced differences between GC+ and GC− ACC, the effects of cortisol on NK cells were assessed in vitro (NK cells from human PBMCs stimulated with IL-2 or IL-12/15). Cortisol suppressed, and relacorilant restored, NK cell activation, proliferation, and direct tumor cell killing. Thus, GR antagonism may increase the abundance and function of NK and other immune cells in the tumor microenvironment, promoting immune response in GC+ ACC and other malignancies with GC+. This hypothesis will be tested in a phase 1 trial of relacorilant + ICI.

Supplementary Materials

    • Supplementary Figure S1
    • Supplementary Figure S2

 

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  • Abercrombie HC, Giese-Davis J, Sephton S, Epel ES, Turner-Cobb JM & Spiegel D 2004 Flattened cortisol rhythms in metastatic breast cancer patients. Psychoneuroendocrinology 29 10821092. (https://doi.org/10.1016/j.psyneuen.2003.11.003)

    • Search Google Scholar
    • Export Citation
  • Aran D, Hu Z & Butte AJ 2017 xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biology 18 220. (https://doi.org/10.1186/s13059-017-1349-1)

    • Search Google Scholar
    • Export Citation
  • Assié G, Letouzé E, Fassnacht M, Jouinot A, Luscap W, Barreau O, Omeiri H, Rodriguez S, Perlemoine K & René-Corail F et al.2014 Integrated genomic characterization of adrenocortical carcinoma. Nature Genetics 46 607612. (https://doi.org/10.1038/ng.2953)

    • Search Google Scholar
    • Export Citation
  • Cirillo N & Prime SS 2011 Keratinocytes synthesize and activate cortisol. Journal of Cellular Biochemistry 112 14991505. (https://doi.org/10.1002/jcb.23081)

    • Search Google Scholar
    • Export Citation
  • Cirillo N, Morgan DJ, Pedicillo MC, Celentano A, Lo Muzio L, McCullough MJ & Prime SS 2017 Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2. British Journal of Cancer 117 984993. (https://doi.org/10.1038/bjc.2017.243)

    • Search Google Scholar
    • Export Citation
  • Else T, Williams AR, Sabolch A, Jolly S, Miller BS & Hammer GD 2014 Adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism 99 455461. (https://doi.org/10.1210/jc.2013-2856)

    • Search Google Scholar
    • Export Citation
  • Gilbert R & Lim EM 2008 The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. Clinical Biochemistry 29 103106.

    • Search Google Scholar
    • Export Citation
  • Habra MA, Stephen B, Campbell M, Hess K, Tapia C, Xu M, Rodon Ahnert J, Jimenez C, Lee JE & Perrier ND et al.2019 Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma. Journal for ImmunoTherapy of Cancer 7 253. (https://doi.org/10.1186/s40425-019-0722-x)

    • Search Google Scholar
    • Export Citation
  • Head L, Kiseljak-Vassiliades K, Clark TJ, Somerset H, King J, Raeburn C, Albuja-Cruz M, Weyant M, Cleveland J & Wierman ME et al.2019 Response to immunotherapy in combination with mitotane in patients with metastatic adrenocortical cancer. Journal of the Endocrine Society 3 22952304. (https://doi.org/10.1210/js.2019-00305)

    • Search Google Scholar
    • Export Citation
  • Jehn CF, Kühnhardt D, Bartholomae A, Pfeiffer S, Schmid P, Possinger K, Flath BC & Lüftner D 2010 Association of IL-6, hypothalamus-pituitary-adrenal axis function, and depression in patients with cancer. Integrative Cancer Therapies 9 270275. (https://doi.org/10.1177/1534735410370036)

    • Search Google Scholar
    • Export Citation
  • Kanehisa M & Goto S 2000 KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Research 28 2730. (https://doi.org/10.1093/nar/28.1.27)

    • Search Google Scholar
    • Export Citation
  • Landwehr LS, Altieri B, Schreiner J, Sbiera I, Weigand I, Kroiss M, Fassnacht M & Sbiera S 2020 Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma. Journal for ImmunoTherapy of Cancer 8 e000469. (https://doi.org/10.1136/jitc-2019-000469)

    • Search Google Scholar
    • Export Citation
  • Liu J, Li XD, Vaheri A & Voutilainen R 2004 DNA methylation affects cell proliferation, cortisol secretion and steroidogenic gene expression in human adrenocortical NCI-H295R cells. Journal of Molecular Endocrinology 33 651662. (https://doi.org/10.1677/jme.1.01560)

    • Search Google Scholar
    • Export Citation
  • Miller AH, Spencer RL, Pearce BD, Pisell TL, Azrieli Y, Tanapat P, Moday H, Rhee R & McEwen BS 1998 Glucocorticoid receptors are differentially expressed in the cells and tissues of the immune system. Cellular Immunology 186 4554. (https://doi.org/10.1006/cimm.1998.1293)

    • Search Google Scholar
    • Export Citation
  • Mormont MC & Lévi F 1997 Circadian-system alterations during cancer processes: a review. International Journal of Cancer 70 241247. (https://doi.org/10.1002/(sici)1097-0215(19970117)70:2<241::aid-ijc16>3.0.co;2-l)

    • Search Google Scholar
    • Export Citation
  • Nicolaides NC, Kino T & Chrousos G 2000 AIDS and HPA axis. In Endotext. Eds Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland J & Kaltsas G et al. South Dartmouth, MA, USA: MDText.com, Inc. (available at: https://www.ncbi.nlm.nih.gov/books/NBK279014/W)

    • Search Google Scholar
    • Export Citation
  • Palesh O, Zeitzer JM, Conrad A, Giese-Davis J, Mustian KM, Popek V, Nga K & Spiegel D 2008 Vagal regulation, cortisol, and sleep disruption in women with metastatic breast cancer. Journal of Clinical Sleep Medicine 4 441449. (https://doi.org/10.5664/jcsm.27280)

    • Search Google Scholar
    • Export Citation
  • Raj N, Zheng Y, Kelly V, Katz SS, Chou J, Do RKG, Capanu M, Zamarin D, Saltz LB & Ariyan CE et al.2020 PD-1 blockade in advanced adrenocortical carcinoma. Journal of Clinical Oncology 38 7180. (https://doi.org/10.1200/JCO.19.01586)

    • Search Google Scholar
    • Export Citation
  • Sharma P, Sandhu SV, Bhandari R, Verma I, Bhullar RK & Khangura RK 2018 Estimation of cortisol levels in patients with premalignant disorders and oral squamous cell carcinoma. Journal of Oral and Maxillofacial Pathology 22 2734. (https://doi.org/10.4103/jomfp.JOMFP_181_16)

    • Search Google Scholar
    • Export Citation
  • Vukelic S, Stojadinovic O, Pastar I, Rabach M, Krzyzanowska A, Lebrun E, Davis SC, Resnik S, Brem H & Tomic-Canic M 2011 Cortisol synthesis in epidermis is induced by IL-1 and tissue injury. Journal of Biological Chemistry 286 1026510275. (https://doi.org/10.1074/jbc.M110.188268)

    • Search Google Scholar
    • Export Citation
  • West DC, Kocherginsky M, Tonsing-Carter EY, Dolcen DN, Hosfield DJ, Lastra RR, Sinnwell JP, Thompson KJ, Bowie KR & Harkless RV et al.2018 Discovery of a glucocorticoid receptor (GR) activity signature using selective GR antagonism in ER-negative breast cancer. Clinical Cancer Research 24 34333446. (https://doi.org/10.1158/1078-0432.CCR-17-2793)

    • Search Google Scholar
    • Export Citation
  • Yaneva M, Kalinov K & Zacharieva S 2013 Mortality in Cushing’s syndrome: data from 386 patients from a single tertiary referral center. European Journal of Endocrinology 169 621627. (https://doi.org/10.1530/EJE-13-0320)

    • Search Google Scholar
    • Export Citation
  • Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA, Lerario AM, Else T, Knijnenburg TA & Ciriello G et al.2016 Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell 29 723736. (https://doi.org/10.1016/j.ccell.2016.04.002)

    • Search Google Scholar
    • Export Citation