Targeting PD-L1 Initiates Effective Antitumor Immunity in a Murine Model of Cushing Disease

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2019 Nov 21

PMID 31744830

Citations 28

Authors

Hanna R Kemeny

Aladine A Elsamadicy

S Harrison Farber

Cosette D Champion

Selena J Lorrey

Pakawat Chongsathidkiet

Karolina I Woroniecka

Xiuyu Cui

Steven H Shen

Kristen E Rhodin

Vadim Tsvankin

Jeffrey Everitt

Luis Sanchez-Perez

Patrick Healy

Roger E McLendon

Patrick J Codd

Ian F Dunn

Peter E Fecci

Affiliations

Soon will be listed here.

Abstract

Purpose: Although pituitary adenoma is classified as benign, Cushing disease is associated with significant morbidity due to the numerous sequelae of elevated cortisol levels. Successful therapy for Cushing disease remains elusive due to high rates of treatment-refractory recurrence. The frequent emergence of lymphocytic hypophysitis following checkpoint blockade for other cancers, as well as the expression of PD-L1 on pituitary adenomas, suggest a role for immunotherapy.

Experimental Design: This study confirms PD-L1 expression on functioning pituitary adenomas and is the first to evaluate the efficacy of checkpoint blockade (anti-PD-L1) therapy in a preclinical model of Cushing disease.

Results: Herein, treatment with anti-PD-L1 was successful in reducing adrenocorticotropic hormone plasma levels, decreasing tumor growth, and increasing survival in our model. Furthermore, tumor-infiltrating T cells demonstrated a pattern of checkpoint expression similar to other checkpoint blockade-susceptible tumors.

Conclusions: This suggests that immunotherapy, particularly blockade of the PD1/PD-L1 axis, may be a novel therapeutic option for refractory Cushing disease. Clinical investigation is encouraged.

Citing Articles

Unlocking Benzosampangine's Potential: A Computational Approach to Investigating, Its Role as a PD-L1 Inhibitor in Tumor Immune Evasion via Molecular Docking, Dynamic Simulation, and ADMET Profiling.

Ouchaoui A, El Hadad S, Aherkou M, Fadoua E, Mouad M, Ramli Y Bioinform Biol Insights. 2024; 18:11779322241298591.

PMID: 39564188 PMC: 11574905. DOI: 10.1177/11779322241298591.

Therapeutical Usefulness of PD-1/PD-L1 Inhibitors in Aggressive or Metastatic Pituitary Tumours.

Lopes-Pinto M, Lacerda-Nobre E, Silva A, Marques P Cancers (Basel). 2024; 16(17).

PMID: 39272895 PMC: 11394371. DOI: 10.3390/cancers16173033.

From Genes to Therapy: Pituitary Adenomas in the Era of Precision Medicine.

Toader C, Dobrin N, Tataru C, Covache-Busuioc R, Bratu B, Glavan L Biomedicines. 2024; 12(1).

PMID: 38275385 PMC: 10813694. DOI: 10.3390/biomedicines12010023.

Aggressive and Metastatic Pituitary Neuroendocrine Tumors: Therapeutic Management and Off-Label Drug Use.

Iglesias P J Clin Med. 2024; 13(1).

PMID: 38202123 PMC: 10779494. DOI: 10.3390/jcm13010116.

PitNETs and the gut microbiota: potential connections, future directions.

Nie D, Li C, Zhang Y Front Endocrinol (Lausanne). 2023; 14:1255911.

PMID: 38027221 PMC: 10657991. DOI: 10.3389/fendo.2023.1255911.

References

Lin A, Jonsson P, Tabar V, Yang T, Cuaron J, Beal K . Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab. J Clin Endocrinol Metab. 2018; 103(10):3925-3930. PMC: 6456994. DOI: 10.1210/jc.2018-01347. View

Hellmann M, Rizvi N, Goldman J, Gettinger S, Borghaei H, Brahmer J . Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2016; 18(1):31-41. PMC: 5476941. DOI: 10.1016/S1470-2045(16)30624-6. View

Lynch T, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R . Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012; 30(17):2046-54. DOI: 10.1200/JCO.2011.38.4032. View

Hodi F, ODay S, Mcdermott D, Weber R, Sosman J, Haanen J . Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363(8):711-23. PMC: 3549297. DOI: 10.1056/NEJMoa1003466. View

Taube J, Klein A, Brahmer J, Xu H, Pan X, Kim J . Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014; 20(19):5064-74. PMC: 4185001. DOI: 10.1158/1078-0432.CCR-13-3271. View

Nguyen S, Castrellon A, Vaidis O, Johnson A . Stereotactic Radiosurgery and Ipilimumab Versus Stereotactic Radiosurgery Alone in Melanoma Brain Metastases. Cureus. 2017; 9(7):e1511. PMC: 5612568. DOI: 10.7759/cureus.1511. View

Shipston M, Antoni F . Early glucocorticoid induction of calmodulin and its suppression by corticotropin-releasing factor in pituitary corticotrope tumor (AtT20) cells. Biochem Biophys Res Commun. 1992; 189(3):1382-8. DOI: 10.1016/0006-291x(92)90227-c. View

Bertagna X, Guignat L . Approach to the Cushing's disease patient with persistent/recurrent hypercortisolism after pituitary surgery. J Clin Endocrinol Metab. 2013; 98(4):1307-18. DOI: 10.1210/jc.2012-3200. View

Pivonello R, Isidori A, De Martino M, Newell-Price J, Biller B, Colao A . Complications of Cushing's syndrome: state of the art. Lancet Diabetes Endocrinol. 2016; 4(7):611-29. DOI: 10.1016/S2213-8587(16)00086-3. View

10.

Wherry E, Ha S, Kaech S, Nicholas Haining W, Sarkar S, Kalia V . Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007; 27(4):670-84. DOI: 10.1016/j.immuni.2007.09.006. View

11.

Butte M, Keir M, Phamduy T, Sharpe A, Freeman G . Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007; 27(1):111-22. PMC: 2707944. DOI: 10.1016/j.immuni.2007.05.016. View

12.

FURTH J, GADSEN E, UPTON A . ACTH secreting transplantable pituitary tumors. Proc Soc Exp Biol Med. 1953; 84(1):253-4. DOI: 10.3181/00379727-84-20607. View

13.

Buliman A, Tataranu L, Paun D, Mirica A, Dumitrache C . Cushing's disease: a multidisciplinary overview of the clinical features, diagnosis, and treatment. J Med Life. 2016; 9(1):12-18. PMC: 5152600. View

14.

Wolchok J, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob J, Cowey C . Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017; 377(14):1345-1356. PMC: 5706778. DOI: 10.1056/NEJMoa1709684. View

15.

Tsushima F, Yao S, Shin T, Flies A, Flies S, Xu H . Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy. Blood. 2007; 110(1):180-5. PMC: 1896111. DOI: 10.1182/blood-2006-11-060087. View

16.

Patil C, Prevedello D, Lad S, Vance M, Thorner M, Katznelson L . Late recurrences of Cushing's disease after initial successful transsphenoidal surgery. J Clin Endocrinol Metab. 2007; 93(2):358-62. DOI: 10.1210/jc.2007-2013. View

17.

Powles T, Eder J, Fine G, Braiteh F, Loriot Y, Cruz C . MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014; 515(7528):558-62. DOI: 10.1038/nature13904. View

18.

Long G, Atkinson V, Lo S, Sandhu S, Guminski A, Brown M . Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 2018; 19(5):672-681. DOI: 10.1016/S1470-2045(18)30139-6. View

19.

Lu J, Adam B, Jack A, Lam A, Broad R, Chik C . Immune Cell Infiltrates in Pituitary Adenomas: More Macrophages in Larger Adenomas and More T Cells in Growth Hormone Adenomas. Endocr Pathol. 2015; 26(3):263-72. DOI: 10.1007/s12022-015-9383-6. View

20.

Okano Y, Satoh T, Horiguchi K, Toyoda M, Osaki A, Matsumoto S . Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma. Endocr J. 2016; 63(10):905-912. DOI: 10.1507/endocrj.EJ16-0161. View