TY  - JOUR
A1  - Landwehr, Laura-Sophie
A1  - Altieri, Barbara
A1  - Schreiner, Jochen
A1  - Sbiera, Iuliu
A1  - Weigand, Isabel
A1  - Kroiss, Matthias
A1  - Fassnacht, Martin
A1  - Sbiera, Silviu
T1  - Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma
JF  - Journal for ImmunoTherapy of Cancer
N2  - Background 
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Tumor-related glucocorticoid excess is present in similar to 60% of patients and associated with particularly poor prognosis. Results of first clinical trials using immune checkpoint inhibitors were heterogeneous. Here we characterize tumor-infiltrating T lymphocytes (TILs) in ACC in association with glucocorticoids as potential explanation for resistance to immunotherapy.

Methods 
We performed immunofluorescence analysis to visualize tumor-infiltrating T cells (CD3\(^+\)), T helper cells (CD3\(^+\)CD4\(^+\)), cytotoxic T cells (CD3\(^+\)CD8\(^+\)) and regulatory T cells (Tregs; CD3\(^+\)CD4\(^+\)FoxP3\(^+\)) in 146 ACC tissue specimens (107 primary tumors, 16 local recurrences, 23 metastases). Quantitative data of immune cell infiltration were correlated with clinical data (including glucocorticoid excess).

Results 
86.3% of ACC specimens showed tumor infiltrating T cells (7.7 cells/high power field (HPF)), including T helper (74.0%, 6.7 cells/HPF), cytotoxic T cells (84.3%, 5.7 cells/HPF) and Tregs (49.3%, 0.8 cells/HPF). The number of TILs was associated with better overall survival (HR for death: 0.47, 95% CI 0.25 to 0.87), which was true for CD4\(^+\)- and CD8\(^+\) subpopulations as well. In localized, non-metastatic ACC, the favorable impact of TILs on overall and recurrence-free survival was manifested even independently of ENSAT (European Network for the Study of Adrenal Tumors) stage, resection status and Ki67 index. T helper cells were negatively correlated with glucocorticoid excess (Phi=-0.290, p=0.009). Patients with glucocorticoid excess and low TILs had a particularly poor overall survival (27 vs. 121 months in patients with TILs without glucocorticoid excess).

Conclusion 
Glucocorticoid excess is associated with T cell depletion and unfavorable prognosis. To reactivate the immune system in ACC by checkpoint inhibitors, an inhibition of adrenal steroidogenesis might be pivotal and should be tested in prospective studies.
KW  - immunity
KW  - immunotherapy
KW  - lymphocytes
KW  - tumor-infiltrating
KW  - t-lymphocytes
KW  - tumor microenvironment
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229893
VL  - 8
ER  - 
TY  - JOUR
A1  - Doghman-Bouguerra, Mabrouka
A1  - Finetti, Pascal
A1  - Durand, Nelly
A1  - Parise, Ivy Zortéa S.
A1  - Sbiera, Silviu
A1  - Cantini, Giulia
A1  - Canu, Letizia
A1  - Hescot, Ségolène
A1  - Figueiredo, Mirna M. O.
A1  - Komechen, Heloisa
A1  - Sbiera, Iuliu
A1  - Nesi, Gabriella
A1  - Paci, Angelo
A1  - Al Ghuzlan, Abir
A1  - Birnbaum, Daniel
A1  - Baudin, Eric
A1  - Luconi, Michaela
A1  - Fassnacht, Martin
A1  - Figueiredo, Bonald C.
A1  - Bertucci, François
A1  - Lalli, Enzo
T1  - Cancer-testis antigen FATE1 expression in adrenocortical tumors is associated with a pervasive autoimmune response and is a marker of malignancy in adult, but not children, ACC
JF  - Cancers
N2  - The SF-1 transcription factor target gene FATE1 encodes a cancer-testis antigen that has an important role in regulating apoptosis and response to chemotherapy in adrenocortical carcinoma (ACC) cells. Autoantibodies directed against FATE1 were previously detected in patients with hepatocellular carcinoma. In this study, we investigated the prevalence of circulating anti-FATE1 antibodies in pediatric and adult patients with adrenocortical tumors using three different methods (immunofluorescence, ELISA and Western blot). Our results show that a pervasive anti-FATE1 immune response is present in those patients. Furthermore, FATE1 expression is a robust prognostic indicator in adult patients with ACC and is associated with increased steroidogenic and decreased immune response gene expression. These data can open perspectives for novel strategies in ACC immunotherapy.
KW  - adrenocortical carcinoma
KW  - cancer-testis antigens
KW  - autoantibodies
KW  - immune response
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203211
SN  - 2072-6694
VL  - 12
IS  - 3
ER  -