Haake et al. found that growth/differentiation factor (GDF)-15 prevents T cells from adhering to, rolling on, and migrating across endothelial cells via the LFA-1/ICAM-1 axis. GDF-15 expression in murine cancer models hastened tumor growth and reduced CD8+ T cell infiltration. Combined anti-GDF-15 and anti-PD-1 treatment induced tumoral T cell infiltration, T cell trafficking to draining lymph nodes, and tumor regression. In human melanoma and HPV+ OPSCC, GDF-15 expression inversely correlated with tumoral T cell infiltration. In patient cohorts treated with immune checkpoint blockade, baseline serum GDF-15 levels predicted treatment response and survival.
Contributed by Maartje Wouters
ABSTRACT: 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/_2-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.
Author Info: (1) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany. (2) Department of Gynecology, University Ho
Author Info: (1) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany. (2) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (3) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (4) German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Neurological Institute (Edinger Institute), University Hospital, Goethe University, Frankfurt/Main, Germany. Frankfurt Cancer Institute (FCI), Frankfurt/Main, Germany. Center for Neuropathology and Prion Research, Munich, Ludwig-Maximilians-University, Munich, Germany. (5) Mildred Scheel Early Career Center, University Hospital of Wrzburg, Wrzburg, Germany. (6) Department of Biotechnology and Biophysics, Julius Maximilians University Wrzburg, Am Hubland, 97074, Wrzburg, Germany. (7) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany. (8) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (9) CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany. (10) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany. (11) Department of Medicine II, University Hospital of Wrzburg, Wrzburg, Germany. (12) Department of Medicine II, University Hospital of Wrzburg, Wrzburg, Germany. (13) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (14) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands. (15) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (16) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (17) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (18) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. Department of Pediatrics, University Hospital Wrzburg, Wrzburg, Germany. (19) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (20) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (21) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (22) CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany. (23) Division of Genetics, Department of Biology, University of Erlangen, 91058, Erlangen, Germany. (24) Division of Genetics, Department of Biology, University of Erlangen, 91058, Erlangen, Germany. (25) Department of Dermatology, University Medical Center Tbingen, Tbingen, Germany. Department of Immunology, University of Tbingen, Tbingen, Germany. Section for Clinical Bioinformatics, Department of Internal Medicine I, University Medical Center Tbingen, Tbingen, Germany. (26) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany. (27) German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Neurological Institute (Edinger Institute), University Hospital, Goethe University, Frankfurt/Main, Germany. Frankfurt Cancer Institute (FCI), Frankfurt/Main, Germany. (28) German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Neurological Institute (Edinger Institute), University Hospital, Goethe University, Frankfurt/Main, Germany. Frankfurt Cancer Institute (FCI), Frankfurt/Main, Germany. Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany. (29) Department of Neuropathology, University of Tbingen, Tbingen, Germany. (30) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands. (31) Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innrain 80, 6020, Innsbruck, Austria. (32) Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innrain 80, 6020, Innsbruck, Austria. (33) Forbion, Naarden, The Netherlands. (34) Department of Dermatology, Venereology and Allergology, University Hospital Wrzburg, Wrzburg, Germany. Clinic for Dermatology and Venereology, Rostock University Medical Center, Rostock, Germany. (35) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany. (36) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. Division of Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63130, USA. (37) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (38) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (39) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (40) CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany. (41) CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany. (42) Department of Dermatology, University of Zurich, University of Zurich Hospital, Wagistrasse 18, 8952, Zrich, Switzerland. (43) Department of Dermatology, University of Zurich, University of Zurich Hospital, Wagistrasse 18, 8952, Zrich, Switzerland. (44) Department of Dermatology, Venereology and Allergology, University Hospital Wrzburg, Wrzburg, Germany. (45) Department of Biotechnology and Biophysics, Julius Maximilians University Wrzburg, Am Hubland, 97074, Wrzburg, Germany. (46) Division of Genetics, Department of Biology, University of Erlangen, 91058, Erlangen, Germany. (47) CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany. (48) oikostat GmbH, Statistical Analyses and Consulting, Lucerne, Switzerland. Department of Biostatistics, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Hirschengraben 84, 8001, Zrich, Switzerland. (49) Department of Oncology (DONC), Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg. Luxembourg Centre of Neuropathology (LCNP), Luxembourg, Luxembourg. National Center of Pathology (NCP), Laboratoire National de Sant (LNS), Dudelange, Luxembourg. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg. Department of Life Sciences and Medicine (DLSM), University of Luxembourg, Luxembourg, Luxembourg. Faculty of Science, Technology and Medicine (FSTM), University of Luxembourg, Esch-sur-Alzette, Luxembourg. (50) Department of Biomedicine and Neurology Department, University Hospital Basel, 4031, Basel, Switzerland. (51) Department of Medicine II, University Hospital of Wrzburg, Wrzburg, Germany. (52) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands. (53) Mildred Scheel Early Career Center, University Hospital of Wrzburg, Wrzburg, Germany. (54) Department of Dermatology, University Medical Center Tbingen, Tbingen, Germany. (55) Forbion, Naarden, The Netherlands. (56) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. Wischhusen_J@ukw.de.
