Expression of CD39 is associated with T cell exhaustion in ovarian cancer and its blockade reverts T cell dysfunction
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Expression of CD39 is associated with T cell exhaustion in ovarian cancer and its blockade reverts T cell dysfunction. / Marius, Witt; Leticia, Oliveira-Ferrer; Friedrich, Koch-Nolte; Stephan, Menzel; Louisa, Hell; Tabea, Sturmheit; Elisa, Seubert; Pauline, Weimer; Yi, Ding; Qi, Minyue; Barbara, Schmalfeldt; Carsten, Bokemeyer; Walter, Fiedler; Jasmin, Wellbrock; Franziska, Brauneck.
in: ONCOIMMUNOLOGY, Jahrgang 13, Nr. 1, 2024, S. 2346359.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Expression of CD39 is associated with T cell exhaustion in ovarian cancer and its blockade reverts T cell dysfunction
AU - Marius, Witt
AU - Leticia, Oliveira-Ferrer
AU - Friedrich, Koch-Nolte
AU - Stephan, Menzel
AU - Louisa, Hell
AU - Tabea, Sturmheit
AU - Elisa, Seubert
AU - Pauline, Weimer
AU - Yi, Ding
AU - Qi, Minyue
AU - Barbara, Schmalfeldt
AU - Carsten, Bokemeyer
AU - Walter, Fiedler
AU - Jasmin, Wellbrock
AU - Franziska, Brauneck
N1 - © 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.
PY - 2024
Y1 - 2024
N2 - Immune exhaustion is a hallmark of ovarian cancer. Using multiparametric flow cytometry, the study aimed to analyze protein expression of novel immunological targets on CD3+ T cells isolated from the peripheral blood (n = 20), malignant ascites (n = 16), and tumor tissue (n = 6) of patients with ovarian cancer (OVCA). The study revealed an increased proportion of effector memory CD8+ T cells in OVCA tissue and malignant ascites. An OVCA-characteristic PD-1high CD8+ T cell population was detected, which differed from PD-1lowCD8+ T cells by increased co-expression of TIGIT, CD39, and HLA-DR. In addition, these OVCA-characteristic CD8+ T cells showed reduced expression of the transcription factor TCF-1, which may also indicate reduced effector function and memory formation. On the contrary, the transcription factor TOX, which significantly regulates terminal T cell-exhaustion, was found more frequently in these cells. Further protein and gene analysis showed that CD39 and CD73 were also expressed on OVCA tumor cells isolated from solid tumors (n = 14) and malignant ascites (n = 9). In the latter compartment, CD39 and CD73 were also associated with the expression of the "don't eat me" molecule CD24 on tumor cells. Additionally, ascites-derived CD24+EpCAM+ tumor cells showed a higher frequency of CD39+ or CD73+ cells. Furthermore, CD39 expression was associated with unfavorable clinical parameters. Expression of CD39 on T cells was upregulated through CD3/CD28 stimulation and its blockade by a newly developed nanobody construct resulted in increased proliferation (eFluor), activation (CD25 and CD134), and production of cytotoxic cytokines (IFN-γ, TNF-α, and granzyme-B) of CD8+ T cells.
AB - Immune exhaustion is a hallmark of ovarian cancer. Using multiparametric flow cytometry, the study aimed to analyze protein expression of novel immunological targets on CD3+ T cells isolated from the peripheral blood (n = 20), malignant ascites (n = 16), and tumor tissue (n = 6) of patients with ovarian cancer (OVCA). The study revealed an increased proportion of effector memory CD8+ T cells in OVCA tissue and malignant ascites. An OVCA-characteristic PD-1high CD8+ T cell population was detected, which differed from PD-1lowCD8+ T cells by increased co-expression of TIGIT, CD39, and HLA-DR. In addition, these OVCA-characteristic CD8+ T cells showed reduced expression of the transcription factor TCF-1, which may also indicate reduced effector function and memory formation. On the contrary, the transcription factor TOX, which significantly regulates terminal T cell-exhaustion, was found more frequently in these cells. Further protein and gene analysis showed that CD39 and CD73 were also expressed on OVCA tumor cells isolated from solid tumors (n = 14) and malignant ascites (n = 9). In the latter compartment, CD39 and CD73 were also associated with the expression of the "don't eat me" molecule CD24 on tumor cells. Additionally, ascites-derived CD24+EpCAM+ tumor cells showed a higher frequency of CD39+ or CD73+ cells. Furthermore, CD39 expression was associated with unfavorable clinical parameters. Expression of CD39 on T cells was upregulated through CD3/CD28 stimulation and its blockade by a newly developed nanobody construct resulted in increased proliferation (eFluor), activation (CD25 and CD134), and production of cytotoxic cytokines (IFN-γ, TNF-α, and granzyme-B) of CD8+ T cells.
KW - Humans
KW - Female
KW - Ovarian Neoplasms/immunology
KW - Apyrase/metabolism
KW - CD8-Positive T-Lymphocytes/immunology
KW - Middle Aged
KW - Ascites/immunology
KW - Antigens, CD/metabolism
KW - Aged
KW - Programmed Cell Death 1 Receptor/metabolism
KW - Receptors, Immunologic/metabolism
KW - T Cell Transcription Factor 1/metabolism
KW - HLA-DR Antigens/metabolism
KW - Adult
KW - T-Cell Exhaustion
KW - High Mobility Group Proteins
U2 - 10.1080/2162402X.2024.2346359
DO - 10.1080/2162402X.2024.2346359
M3 - SCORING: Journal article
C2 - 38737794
VL - 13
SP - 2346359
JO - ONCOIMMUNOLOGY
JF - ONCOIMMUNOLOGY
SN - 2162-402X
IS - 1
ER -