Abstract 2161: Identifying GDF-15 as potential novel immunotherapeutic target linked to immune cell exclusion in tumors and resistance to anti-PD-1 treatment

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.

Plasma GDF15 levels associated with circulating immune cells predict the efficacy of PD-1/PD-L1 inhibitor treatment and prognosis in patients with advanced non-small cell lung cancer

“…GDF15 is a stress-induced cytokine secreted by tumor cells that is affected by tumor-promoting inflammation and immune infiltration (Zhou et al 2013 ). In a previous study on the predictive role of GDF15 in anti-PD1 treatment in patients with melanoma, intratumoral GDF15 levels in melanoma correlated inversely with CD3 + and CD8 + T cell infiltration (Wischhusen et al 2020a , b ). In murine prostate cancer, GDF15 overexpression was associated with increased CD8 + T cell numbers and a reduced proportion of CD8 + PD-1 + T cells (Husaini et al 2020 ).…”

“…Additionally, evaluation for the value of GDF15 in lung cancer chemotherapeutic response showed that GDF15 levels were significantly decreased in all patients after two cycles of treatment, regardless of the type of response to treatment; the effect was greater in the PR group (Deng et al 2021 ). In an abstract presented at the 2020 American Association for Cancer Research, it was reported that GDF15 levels in patients with melanoma were predictive of the clinical response to anti-PD1 treatment (Wischhusen et al 2020a , b ). However, since the entire paper has not been published, the cutoff value of GDF15 levels, treatment response, and survival data cannot be accurately established, and the change in GDF15 levels has not been studied.…”

“…Recently, an emerging role for GDF15 in immune cell phenotypes of various diseases has been identified (Wischhusen et al 2020a , b ). The depletion of tumor-derived GDF15—directly regulated by NF-κB—in an orthotopic pancreatic cancer model restored the immune surveillance function of tumor-infiltrating macrophages, resulting in improved tumor control (Ratnam et al 2017 ).…”

“…GDF15 is known to promote immune escape of tumor cells by inhibiting T cell stimulation and cytotoxic T lymphocyte activation (Haake et al 2022 ). Although it has been reported that GDF15 expression in human tumor tissues is associated with CD3+ or CD8+ T cell infiltration (Wischhusen et al 2020a , b ), the effect of circulating GDF15 on immune escape signaling remains largely unknown. In the present study, we investigated whether GDF15 levels can be a predictive marker in patients with NSCLC treated with PD-1/PD-L1 inhibitors and identified the association between circulating GDF15 levels and immune cell populations of peripheral blood mononuclear cells (PBMCs).…”

EstroGene database reveals diverse temporal, context-dependent and directional estrogen receptor regulomes in breast cancer

“…By mining single-cell RNA-seq profiling of series biopsies from an anti-PD-1 treated breast cancer cohort, we further found that the E2 response plasticity might be used by cancer cells to facilitate their escape from immune surveillance, while it may not affect endocrine therapy outcomes. For example, the induction of GDF15 with anti-PD-1 exposure could largely cause immune suppression via CD44-mediated suppression of dendritic cells maturation(58) and blockade of cytotoxic T cell recruitment(59). This is consistent with a previous report describing the role of ER signaling in suppressing cancer immune response(60).…”