TY  - JOUR
A1  - Haake, Markus
A1  - Haack, Beatrice
A1  - Schäfer, Tina
A1  - Harter, Patrick N.
A1  - Mattavelli, Greta
A1  - Eiring, Patrick
A1  - Vashist, Neha
A1  - Wedekink, Florian
A1  - Genssler, Sabrina
A1  - Fischer, Birgitt
A1  - Dahlhoff, Julia
A1  - Mokhtari, Fatemeh
A1  - Kuzkina, Anastasia
A1  - Welters, Marij J. P.
A1  - Benz, Tamara M.
A1  - Sorger, Lena
A1  - Thiemann, Vincent
A1  - Almanzar, Giovanni
A1  - Selle, Martina
A1  - Thein, Klara
A1  - Späth, Jacob
A1  - Gonzalez, Maria Cecilia
A1  - Reitinger, Carmen
A1  - Ipsen-Escobedo, Andrea
A1  - Wistuba-Hamprecht, Kilian
A1  - Eichler, Kristin
A1  - Filipski, Katharina
A1  - Zeiner, Pia S.
A1  - Beschorner, Rudi
A1  - Goedemans, Renske
A1  - Gogolla, Falk Hagen
A1  - Hackl, Hubert
A1  - Rooswinkel, Rogier W.
A1  - Thiem, Alexander
A1  - Romer Roche, Paula
A1  - Joshi, Hemant
A1  - Pühringer, Dirk
A1  - Wöckel, Achim
A1  - Diessner, Joachim E.
A1  - Rüdiger, Manfred
A1  - Leo, Eugen
A1  - Cheng, Phil F.
A1  - Levesque, Mitchell P.
A1  - Goebeler, Matthias
A1  - Sauer, Markus
A1  - Nimmerjahn, Falk
A1  - Schuberth-Wagner, Christine
A1  - Felten, Stefanie von
A1  - Mittelbronn, Michel
A1  - Mehling, Matthias
A1  - Beilhack, Andreas
A1  - van der Burg, Sjoerd H.
A1  - Riedel, Angela
A1  - Weide, Benjamin
A1  - Dummer, Reinhard
A1  - Wischhusen, Jörg
T1  - Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment
JF  - Nature Communications
N2  - Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.
KW  - cancer microenvironment
KW  - immunotherapy
KW  - T cells
KW  - tumour immunology
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357333
VL  - 14
ER  - 
TY  - JOUR
A1  - Thiem, Alexander
A1  - Hesbacher, Sonja
A1  - Kneitz, Hermann
A1  - di Primio, Teresa
A1  - Heppt, Markus V.
A1  - Hermanns, Heike M.
A1  - Goebeler, Matthias
A1  - Meierjohann, Svenja
A1  - Houben, Roland
A1  - Schrama, David
T1  - IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression
JF  - Journal of Experimental & Clinical Cancer Research
N2  - Background
Immune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma.

Methods
We analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway.

Results
For TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53\(^{L22Q,W23S}\), a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53\(^{L22Q,W23S}\) in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression.

Conclusions
While having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy.
KW  - Melanoma
KW  - PD-L1
KW  - CD274
KW  - p53
KW  - TP53
KW  - JAK2
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201016
VL  - 38
ER  -