Tumor-derived GDF-15 to suppress t-lymphocyte recruitment to the tumor microenvironment resulting in resistance to ANTI-PD-1 treatment.

person Joerg Wischhusen University of Wuerzburg, Department of Gynecology and Obstetrics, Würzburg, Germany info_outline Joerg Wischhusen, Markus Haake, Neha Vashist, Sabrina Genßler, Kilian Wistuba-Hamprecht, Patrick Harter, Alexander Martens, Michel Mittelbronn, Mitchell P. Levesque, Reinhard Dummer, Benjamin Weide, Marij JP Welters, Sjoerd H van der Burg, Manfred Ruediger, Eugen Leo, Falk Nimmerjahn, Christine Schuberth-Wagner

Authors person Joerg Wischhusen University of Wuerzburg, Department of Gynecology and Obstetrics, Würzburg, Germany info_outline Joerg Wischhusen, Markus Haake, Neha Vashist, Sabrina Genßler, Kilian Wistuba-Hamprecht, Patrick Harter, Alexander Martens, Michel Mittelbronn, Mitchell P. Levesque, Reinhard Dummer, Benjamin Weide, Marij JP Welters, Sjoerd H van der Burg, Manfred Ruediger, Eugen Leo, Falk Nimmerjahn, Christine Schuberth-Wagner Organizations University of Wuerzburg, Department of Gynecology and Obstetrics, Würzburg, Germany, CatalYm GmbH, Planegg-Martinsried, Germany, University of Tübingen, Tübingen, Germany, German Cancer Consortium, Frankfurt, Germany, University of Tuebingen, Tuebingen, Germany, University of Luxembourg, Luxembourg, Luxembourg, University Hospital Zurich, Zurich, Switzerland, Skin Cancer Center, University Hospital of Zürich, Zürich, Switzerland, Department of Dermatology, University Hospital Tübingen, Tübingen, Germany, Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands, Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands, T-Knife GmbH, Berlin, Germany, University of Erlangen, Erlangen, Germany, CatalYm GmbH, Planegg/Munich, Germany Abstract Disclosures Research Funding Pharmaceutical/Biotech Company CatalYm GmbH Background: Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily with low to absent expression in healthy tissue. GDF-15 has been linked to feto-maternal immune tolerance, to prevention of excessive immune cell infiltration during tissue damage, and to anorexia. Various major tumor types secrete high levels of GDF-15. In cancer patients, elevated GDF-15 serum levels correlate with poor prognosis and reduced overall survival (OS). Methods: Impact of a proprietary GDF-15 neutralizing antibody (CTL-002) regarding T cell trafficking was analyzed by whole blood adhesion assays, a HV18-MK melanoma-bearing humanized mouse model and a GDF-15-transgenic MC38 model. Additionally, patient GDF-15 serum levels were correlated with clinical response and overall survival in oropharyngeal squamous cell carcinoma (OPSCC) and melanoma brain metastases. Results: In whole blood cell adhesion assays GDF-15 impairs adhesion of T and NK cells to activated endothelial cells. Neutralization of GDF-15 by CTL-002 rescued T cell adhesion. In HV18-MK-bearing humanized mice CTL-002 induced a strong increase in TIL numbers. Subset analysis revealed an overproportional enrichment of T cells, in particular CD8 + T cells. As immune cell exclusion is detrimental for checkpoint inhibitor (CPI) therapy, a GDF-15-transgenic MC38 model was tested for anti-PD-1 therapy efficacy. In GDF-15 overexpressing MC38 tumors response to anti PD-1 therapy was reduced by 90% compared to wtMC38 tumors. Combining aPD-1 with CTL-002 resulted in 50% of the mice rejecting their GDF-15 overexpressing tumors. Clinically, inverse correlations of GDF-15 levels with CD8 + T cell infiltration were shown for HPV + OPSCC and for melanoma brain metastases. GDF-15 serum levels were significantly higher in HPV- than in HPV+ OPSCC patient (p < 0.0001). Low GDF-15 levels corresponded to longer OS in both HPV- and HPV+ OPSCC. In two independent melanoma patient cohorts treated with nivolumab or pembrolizumab low baseline serum GDF-15 levels were predictive for clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 independently predicts poor survival in aPD-1 treated melanoma patients. Conclusions: Taken together our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of T cells to extravasate blood vessels and enter tumor tissue both in vitro and in vivo . In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. GDF-15 may thus serve as a new predictive biomarker for anti-PD1 response, but most importantly also represents a novel target for cancer immunotherapy to improve tumor immune cell infiltration and response to anti-PD1 therapy.