Abstract Introduction: Growth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member mainly expressed in placenta and prostate of healthy individuals. GDF-15 has been linked to feto-maternal tolerance, prevention of excessive immune cell infiltration during tissue damage and to anorexia. In cancer patients, GDF-15 serum levels are frequently elevated and associated with poor prognosis, via so far mostly unknown mechanism(s). A recent study elucidated a mechanism by which GDF-15 inhibits LFA-1 activation on CD8+ T cells, thus interfering with T cell recruitment to tissues Haake et al. AACR 2020; submitted. To further delineate the role of GDF-15 in cancer in this study GDF-15 serum and tissue levels were analyzed and correlated with tumoral immune-cell infiltration and clinical anti-PD1 response. Methods: In-silico, TCGA-derived mRNA levels of GDF-15 were compared in cancer vs. normal tissue. Two independent melanoma patient cohorts (88 and 34 patients) treated with nivolumab or pembrolizumab were analyzed regarding baseline GDF-15 serum levels, correlation with clinical response and overall survival. Melanoma brain metastases from 80 patients were collected to assess and compare intratumoral GDF-15 levels vs. CD3+, CD8+ and Foxp3+ cell numbers by immunohistochemistry (IHC). Results: TCGA-based analyses demonstrated significantly elevated GDF-15 mRNA levels in tumor vs. surrounding normal tissue in various major cancer types such as e.g. colorectal, prostate, head & neck and melanoma. In the two independent, anti-PD1 treated melanoma patient cohorts baseline serum GDF-15 levels were predictive for superior overall survival and clinical response to anti-PD1 treatment (p<0.0001 and p=0.0382, respectively). In melanoma biopsies an inverse correlation of GDF-15 levels (histoscore) with CD3+ (R=-0.26; p=0.016) and CD8+ T cells (R=-0.21; p=0.05), but no correlation with Foxp3+ T cells was shown. Conclusion: GDF-15 is elevated in serum and tumor tissue of various major cancer types. In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. In addition, intratumoral GDF-15 levels in melanoma brain metastasis correlate inversely with CD3+ and CD8+ T cell infiltration. Consequently, GDF-15 may serve as a predictive biomarker for anti-PD1 response and potentially represent a novel target in the immunotherapy of cancer to improve tumor immune cell infiltration and anti-PD1 response. Citation Format: Jorg Wischhusen, Kilian Wistuba-Hamprecht, Patrick N. Harter, Phil Cheng, Alexander Martens, Falk Gogolla, Yumi Nonomura, Paula Romer, Sven D. Koch, Markus Haake, Christine Schuberth-Wagner, Manfred Rudiger, Eugen Leo, Michael Mittelbronn, Mitchell P. Levesque, Hubert Hackl, Reinhard Dummer, Benjamin Weide. Identifying GDF-15 as potential novel immunotherapeutic target linked to immune cell exclusion in tumors and resistance to anti-PD-1 treatment abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2161.