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

被引：40

作者：

Lang, Julie ^{[1
]}

Capasso, Anna ^{[2
]}

Jordan, Kimberly R. ^{[1
]}

French, Jena D. ^{[3
]}

Kar, Adwitiya ^{[3
]}

Bagby, Stacey M. ^{[2
]}

Barbee, Jacob ^{[1
]}

Yacob, Betelehem W. ^{[2
]}

Head, Lia S. ^{[2
]}

Tompkins, Kenneth D. ^{[3
]}

Freed, Brian M. ^{[1
]}

Somerset, Hilary ^{[4
]}

Clark, Toshimasa J. ^{[5
]}

Pitts, Todd M. ^{[2
]}

Messersmith, Wells A. ^{[2
]}

Eckhardt, S. Gail ^{[7
]}

Wierman, Margaret E. ^{[3
,6
]}

Leong, Stephen ^{[2
]}

Kiseljak-Vassiliades, Katja ^{[3
,6
]}

机构：

[1] Univ Colorado, Dept Immunol & Microbiol, Sch Med, Anschutz Med Campus, Aurora, CO 80045 USA

[2] Univ Colorado, Div Med Oncol, Dept Med, Sch Med, Colorado Anschutz Med Campus, Aurora, CO 80045 USA

[3] Univ Colorado, Div Endocrinol Metab & Diabet, Dept Med, Sch Med, Colorado Anschutz Med Campus, Aurora, CO 80045 USA

[4] Univ Colorado, Dept Pathol, Sch Med, Colorado Anschutz Med Campus, Aurora, CO 80045 USA

[5] Univ Colorado, Dept Radiol, Sch Med, Colorado Anschutz Med Cam, Aurora, CO 80045 USA

[6] Res Serv Vet Affairs Med Ctr, Denver, CO 80220 USA

[7] Univ Texas Austin, Dell Med Sch, Austin, TX 78701 USA

来源：

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM | 2020年 / 105卷 / 01期

关键词：

Adrenocortical carcinoma; anti-PD-1; humanized mouse PDX model; immunotherapy; MULTIPLEXED IMMUNOHISTOCHEMISTRY; XENOGRAFT MODELS; T-CELLS; CARCINOMA; MICE; NIVOLUMAB; RECONSTITUTION; IMMUNOTHERAPY; IPILIMUMAB; EXPRESSION;

D O I：

10.1210/clinem/dgz014

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-Rag2(null)Il2r gamma(null)Sirpa(NOD) 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.

引用

页码：26 / 42

页数：17