Development of an Adrenocortical Cancer Humanized Mouse Model to Characterize Anti-PD1 Effects on Tumor Microenvironment

J Clin Endocrinol Metab. 2020 Jan 1;105(1):26-42. doi: 10.1210/clinem/dgz014.


Context: Although the development of immune checkpoint inhibitors has transformed treatment strategies of several human malignancies, research models to study immunotherapy in adrenocortical carcinoma (ACC) are lacking.

Objective: To explore the effect of anti-PD1 immunotherapy on the alteration of the immune milieu in ACC in a newly generated preclinical model and correlate with the response of the matched patient.

Design, setting, and intervention: To characterize the CU-ACC2-M2B patient-derived xenograft in a humanized mouse model, evaluate the effect of a PD-1 inhibitor therapy, and compare it with the CU-ACC2 patient with metastatic disease.

Results: Characterization of the CU-ACC2-humanized cord blood-BALB/c-Rag2nullIl2rγnullSirpaNOD model confirmed ACC origin and match with the original human tumor. Treatment of the mice with pembrolizumab demonstrated significant tumor growth inhibition (60%) compared with controls, which correlated with increased tumor infiltrating lymphocyte activity, with an increase of human CD8+ T cells (P < 0.05), HLA-DR+ T cells (P < 0.05) as well as Granzyme B+ CD8+ T cells (<0.001). In parallel, treatment of the CU-ACC2 patient, who had progressive disease, demonstrated a partial response with 79% to 100% reduction in the size of target lesions, and no new sites of metastasis. Pretreatment analysis of the patient's metastatic liver lesion demonstrated abundant intratumoral CD8+ T cells by immunohistochemistry.

Conclusions: Our study reports the first humanized ACC patient-derived xenograft mouse model, which may be useful to define mechanisms and biomarkers of response and resistance to immune-based therapies, to ultimately provide more personalized care for patients with ACC.

Keywords: Adrenocortical carcinoma; anti-PD-1; humanized mouse PDX model; immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adrenal Cortex Neoplasms / drug therapy*
  • Adrenal Cortex Neoplasms / immunology
  • Adrenal Cortex Neoplasms / pathology
  • Adrenocortical Carcinoma / drug therapy*
  • Adrenocortical Carcinoma / immunology
  • Adrenocortical Carcinoma / pathology
  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antineoplastic Agents, Immunological / pharmacology
  • Apoptosis
  • Cell Proliferation
  • Disease Models, Animal*
  • Female
  • Humans
  • Immunotherapy
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • Tumor Cells, Cultured
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology*
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • pembrolizumab