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The impact of the expression level of growth differentiation factor 15 in tumor tissue on the response to immunotherapy in non-small cell lung cancer

BMC Cancer volume 24, Article number: 954 (2024) Cite this article

Abstract

Background

Growth differentiation factor-15 (GDF-15), a member of the TGF-β superfamily, is overexpressed in various cancers and facilitates immune evasion by inhibiting T-cell activation. GDFATHER-TRIAL’s phase 2a results demonstrated promising outcomes when combining the GDF-15 neutralizing antibody visugromab (CTL002) with nivolumab, enhancing the response to immunotherapy. This study evaluated the prognostic significance of GDF-15 expression in non-small cell lung cancer (NSCLC) tumor tissues in terms of immunotherapy response.

Methods

This retrospective study included 50 patients with metastatic NSCLC treated with nivolumab at Gazi University Hospital between January 2021 and July 2023. GDF-15 expression was evaluated using immunochemistry staining and categorized based on the intensity of cytoplasmic or membranous staining. Samples were divided into a low expression group (scores 0 and 1) and a high expression group (scores 2 and 3). The primary outcomes were progression-free survival (PFS) and overall survival (OS), which were analyzed using Kaplan‒Meier and Cox proportional hazards models. Objective response rates were assessed in secondary outcomes.

Results

Of the 50 patients, 43 were men (86%), with a median age of 63.9 years. Half of the patients exhibited low GDF-15 expression. High GDF-15 expression correlated with shorter PFS and OS. The median PFS was 7.8 months for the low-expression group versus 4.4 months for the high-expression group (HR, 0.41; 95% CI, 0.20–0.83; p = 0.013). The median OS was 18.1 months for the low-expression group compared to 11.8 months for the high-expression group (HR, 0.36; 95% CI, 0.16–0.78; p = 0.007). The objective response rate was significantly greater in the low GDF-15 group (52%) than in the high GDF-15 group (24%) (p = 0.040).

Conclusion

Elevated GDF-15 expression in NSCLC tumor tissues is associated with poorer response to nivolumab, suggesting that GDF-15 is a potential prognostic biomarker for immunotherapy efficacy. These findings warrant further validation through prospective studies to optimize treatment strategies for NSCLC patients.

Peer Review reports

Introduction

Growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1, is part of the transforming growth factor-beta (TGF-β) superfamily [1]. It is notably overexpressed in various human cancers, although its presence in somatic tissues such as the lungs is rare [2, 3]. Like TGF-β, GDF-15 is known for its anti-inflammatory properties. It inhibits T-cell activation by cytotoxic T lymphocytes and dendritic cells, thereby facilitating tumor cell evasion from immune surveillance [1, 4, 5]. Recent extensive research highlighting the role of GDF-15 in tumor immunosuppression has led to therapeutic trials targeting this protein. Notably, the phase 2a results of GDFATHER-TRIAL demonstrated promising outcomes when the GDF-15 neutralizing antibody visugromab (CTL002) was combined with nivolumab, enhancing the response to immunotherapy. GD-FATHER-TRIAL demonstrated the efficacy of visugromab in combination with nivolumab in different tumor types, including NSCLC, bladder cancer and malignant melanoma [6].

Unless contraindicated, the management of advanced NSCLC is a combination of first-line immunotherapy and chemotherapy [7]. In our country, for nivolumab treatment to be covered by reimbursement, the patient must have previously received a platinum-based chemotherapy regimen, and the disease must have progressed during or after this treatment. In our country, as in a significant part of the world population, chemoimmunotherapy cannot be given as a first-line treatment due to economic conditions. Access to immunotherapy poses a significant challenge for low- and middle-income countries [8, 9]. For instance, a study in Colombia reported that only 1.9% of patients received chemoimmunotherapy as a first-line treatment for NSCLC [10]. Conversely, in developed countries, access to first-line treatment varies due to socioeconomic disparities. A study in the United States demonstrated that NSCLC patients living in low-income areas had 30% less access to chemo immunotherapy [11]. Consequently, selecting patients who will benefit most from chemoimmunotherapy is crucial in today’s context of limited immunotherapy access.

Nivolumab blocks the PD-1 protein and has shown broad efficacy and a manageable safety profile in various cancers [12,13,14,15,16]. Factors such as a PDL-1 expression over 50%, good performance status, and no driver mutations are critical in predicting immunotherapy success in NSCLC patients. Research continues to refine predictive markers for tailoring treatment strategies [12, 13, 17].

This study evaluated the potential of GDF-15 expression in NSCLC tumor tissues as a prognostic marker for immunotherapy response.

Methods

Study design

This study aimed to evaluate the expression level of GDF-15 in metastatic NSCLC tissues using immunohistochemistry and the relationship between its expression level and response to nivolumab. This was a retrospective investigation conducted at a single center at Gazi University Hospital. The study was conducted in accordance with the Helsinki declaration and was completed with the approval of the ethics committee of Gazi University, with the assigned approval number E-77082166-604.01.02-763671. Consent from patients was unnecessary due to the retrospective nature of the study, as determined by the ethics committee.

The cohort included adults aged 18 years and older who were diagnosed with metastatic NSCLC and who received immunotherapy at the Gazi University Faculty of Medicine Oncology Clinic from January 2021 to July 2023. All metastatic NSCLC patients were included in the study, regardless of the metastasis site, and only those with active brain metastases at the time of diagnosis were excluded, as it would affect the survival time regardless of treatment. Exclusion criteria: Patients diagnosed only by cytology, whose tissue was not available at our center, and whose performance status was too poor to receive systemic treatment were excluded from the study. Patients with driver mutations were excluded. The first-line regimens of carboplatin + paclitaxel, gemcitabine + cisplatin, or cisplatin + pemetrexed were administered to the patients. Nivolumab treatment was initiated as a second-line treatment if radiological progression according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria was found in systemic imaging (CT or PET) examined every three cycles during treatment follow-up [18]. The study did not include patients who received first-line immunotherapy, other forms of immunotherapy in addition to nivolumab, more than one line of chemotherapy prior to immunotherapy, or combined chemotherapy with their immunotherapy regimen.

Responses to nivolumab treatment were evaluated according to RECIST criteria version 1.1 in accordance with the literature [18].

The data analyzed included pretreatment variables such as age, sex, Eastern Cooperative Oncology Group Scale of Performance Status (ECOG-PS), histologic subtype, and PD-L1 expression level.

Immunohistochemical method

The tumor tissue in the material was confirmed by two pathologists (B.Ö. and N.A.) who re-evaluated the selection of paraffin-embedded, formalin-fixed tissue sections from patients diagnosed with NSCLC. After the confirmation of tumor tissue in the material, the appropriate blocks were chosen for the purpose of the study. The selected tumor blocks exhibited high tumor cell density and minimal necrosis. Four-micron-thick sections, fixed in 10% formalin and embedded in paraffin, were mounted on positively charged slides. Deparaffinization of the sections was followed by incubation with an anti-GDF-15 antibody (sc-377195; Santa Cruz Biotechnology Inc., Dallas, TX, USA), a mouse monoclonal antibody targeting amino acids 1-308, representing the full-length human GDF-15 protein. Immunohistochemistry analysis also included ten surgical tissue sections from patients without advanced NSCLC, using a segment of normal human placental tissue as a positive control to ensure consistency.

Scoring of positive cells

A positive immunoreaction for GDF-15 was defined by cytoplasmic or membranous expression in lung cancer cells. Two pathologists evaluated GDF-15 expression, categorizing staining intensity based on a methodology adapted from Morita-Tanaka et al. [19]. Initially, all tumor regions were examined. Subsequently, the density was assessed in a randomly selected ×400 high-power field. Staining intensity was classified as follows: an IHC score of 0 indicated no staining; 1 + indicated partial staining; 2 + denoted diffuse, weak-to-moderate staining; and 3 + represented widespread, strong staining, visible at 40x magnification (Fig. 1). Based on these criteria, patients were divided into two groups: a GDF-15-low-expression group (scores of 0 or 1+) and a GDF-15-high-expression group (scores of 2 + and 3+).

Fig. 1
figure 1

Microscopic View of GDF-15 Expression. A, B. The staining intensity in sparse cells (approximately 5%) was graded as 1. C. In the prevalent cell population (approximately 10%), the staining intensity was graded as 1. D. Approximately 60% of cells exhibited expression at intensity level 3

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Statistical analysis

Categorical variables, including the clinical and demographic characteristics of the patients, were summarized using frequencies and percentages. Continuous variables are described using either the mean ± standard deviation (SD) or the median and interquartile range, as appropriate. The chi-square test, or Fisher’s exact test for smaller sample sizes, was used to compare categorical variables between the low-GDF-15 and high-GDF-15 expression groups. For continuous variables, comparisons were made using either Student’s t test or the Wilcoxon rank-sum test, depending on the data distribution.

Progression-free survival (PFS) was defined as the time from the initiation of nivolumab treatment to the occurrence of disease progression or last follow-up, and overall survival (OS) was measured from the start of Nivolumab treatment to the date of death or last follow-up. Survival estimates were calculated using the Kaplan‒Meier method, with the median survival times depicted in Kaplan‒Meier curves.

The log-rank test was used to compare survival curves between groups. Multivariate analysis included variables that reached a significance level of P < 0.10 in the univariate analysis. The significance threshold for all tests was set at a p value of less than 0.05. The Cox proportional hazards model was utilized to evaluate the associations between expression groups and survival outcomes, with the results reported as hazard ratios (HRs) and 95% confidence intervals (CIs). All the statistical analyses were conducted using SPSS version 27.

Results

Patient characteristics

A total of 50 patients were included in this study, 43 (86%) of whom were men and 7 (14%) of whom were women. The median age of the participants was 63.9 years (48–79). Four patients had recurrent disease, and 92% of patients were denovo metastatic. The four patients had undergone surgery previously. GDF-15 expression in tumor tissues was classified as low in half of the patients. Regarding histopathological types, 30 patients (60%) had adenocarcinoma, and 20 (40%) had squamous cell carcinoma. The detailed patient characteristics are summarized in Table 1.

Table 1 Patient demographic and pathological features
Full size table

Survival analysis

The median follow-up duration for our study was 19.2 months (95% CI: 3.2–35.2). According to the first-line chemotherapy response analysis, the group with high GDF-15 expression had a median PFS of 7.3 months (95% CI: 2.4–12.2), while the group with low GDF-15 expression had a median PFS of 5.2 months (95% CI: 4.2–6.2) (p = 0.065).

Patients treated with nivolumab had a median duration of therapy of 5.2 months. The median PFS was 7.8 months (95% CI 0.5–17.6) in the low GDF-15-expressing group and 4.4 months (95% CI 3.5–5.2) in the high GDF-15-expressing group (HR, 0.41; 95% CI, 0.20 to 0.83; p = 0.013) (Fig. 2). The objective response rate was significantly greater in the low-GDF-15-expressing group, with thirteen patients (52%) achieving an objective response compared to six patients (24%) in the high-GDF-15-expressing group (p = 0.040). (Table 2)

Fig. 2
figure 2

Kaplan‒Meier curves for progression–free survival

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Table 2 Univariate analyses of factors for the prognosis of progression-free survival
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The median OS across all patients was 12.9 months (95% CI 10.8–15.0). The low GDF-15 expression group exhibited a median OS of 18.1 months (95% CI 2.2–34.0), whereas it was 11.8 months (95% CI 8.5–15.1) in the high GDF-15 expression group (HR, 0.36; 95% CI, 0.16 to 0.78; p = 0.007) (Fig. 3). Cox regression analysis was used to examine the relationship between prognostic variables and OS, revealing no significant differences between groups based on ECOG performance score, age, histologic subtype, or PDL1 level (p > 0.05). (Table 3)

Fig. 3
figure 3

Kaplan‒Meier curves for overall survival

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Table 3 Univariate analyses of factors associated with overall survival
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Following progression on nivolumab, 52% of the patients received docetaxel, 12% were administered weekly carboplatin-paclitaxel, and 36% opted for best supportive care as third-line treatment.

Discussion

This study confirmed the relationship between GDF-15 expression levels and response to immunotherapy in advanced NSCLC patients. Our study demonstrated a statistically significant relationship between tumors with high GDF-15 levels and shorter PFS, shorter OS, and worse objective treatment responses with nivolumab. In line with prior preclinical research, our findings suggest that elevated GDF-15 expression correlates with a reduced response to treatment, suggesting that GDF-15 could be a valuable prognostic marker for nivolumab efficacy in NSCLC patients.

Experimental research has shown that GDF-15 acts as a potent inhibitor of dendritic cell maturation, impeding the expression of major histocompatibility complex (MHC) class II molecules and costimulatory molecules. This diminishing IL-12 levels, and enhancing TGF-β1 secretion [20, 21]. Consequently, GDF-15 may promote immune evasion by inhibiting T-cell activation mediated by dendritic cells and cytotoxic T lymphocytes [20,21,22,23,24]. The role of GDF-15 in facilitating tumor immune evasion, as supported by extensive literature, aligns with the outcomes of our study.

Increased blood levels of GDF-15 were linked to poorer survival outcomes in a study by Liu et al. that included 152 patients with non-small cell lung cancer [25]. However, the use of serum GDF-15 as a prognostic marker is limited because it is affected by a number of outside variables, including age, infection, stress, and heart failure [3, 25, 26]. Consequently, tumor-specific GDF-15 is becoming a more reliable marker for determining prognosis in NSCLC patients since it is not affected by these factors.

Blood GDF-15 levels, which are influenced by a variety of factors, and GDF-15 expression in tumor tissue are significantly clinically related to cachexia. Through its interaction with the GFRAL receptor in the brainstem region, GDF-15 in the blood has been implicated in the development of cancer-associated cachexia by influencing appetite and weight management. The occurrence in question has been described as a cytokine reaction in which GDF-15 levels are involved [27,28,29]. Cachexia has been linked to decreased overall survival and progression-free survival among patients with NSCLC. Nevertheless, objective immunotherapy response rates remain comparable [30, 31]. In contrast, there was no significant correlation between the expression level of GDF-15 in tumor tissue and cachexia, as opposed to blood serum levels. This finding suggested that the level of GDF-15 within tumor tissue could function as a more accurate marker for evaluating treatment efficacy and resistance to immunotherapy [19].

Programmed death-ligand 1 has become a widely recognized target for immunotherapy in the treatment of lung cancer, particularly NSCLC. The popularity of PD-L1 as a therapeutic target is attributed to its crucial role in the immune system’s ability to detect and eliminate cancer cells [32, 33]. Studies have demonstrated the significant impact of PD-L1 inhibitors in improving survival rates and treatment outcomes for NSCLC patients [34,35,36]. These effective results of PD-L1 inhibitors have become the most popular area of research in the field of immunotherapy for cancer treatment. Although immunotherapy plays a substantial role in improving patient survival, the specific patients who will exhibit favorable responses to this approach remain undetermined. Although prognostic indicators such as PD-L1 levels exceeding 50% and Eastern Cooperative Oncology Group performance scores have demonstrated utility in predicting immunotherapy response, the precise patients who will receive substantial benefits from immunotherapy remain uncertain [33, 37, 38]. This uncertainty stems from the complex structure of the tumor microenvironment, tumor escape mechanisms from the immune system, and the multifactorial effects that can manifest on the immune system [39,40,41,42,43]. According to preclinical research, tumors exhibiting elevated levels of GDF15 expression remain relatively unresponsive to PD-1-targeted immune checkpoint blockade therapy [44]. It is hypothesized that GDF-15 mediates immunotherapy resistance in the tumor microenvironment via its anti-inflammatory effects. The data obtained from the phase 2 results of the Visugromab trials support the hypothesis that GDF-15 neutralization could enhance the response to immunotherapy [6]. Consequently, we believe that GDF-15, an indicator that contributes to the mechanism of immunotherapy resistance, is a valuable biomarker for predicting treatment response and directing the selection of patients who will receive Visugromab when combined with immunotherapy.

The findings of our study indicate that individuals exhibiting elevated levels of GDF-15 expression within tumor tissue exhibit a poor response to the administration of the single agent nivolumab. Consequently, these patients derive limited benefits from single-agent immunotherapy. The potential of GDF-15 expression in tumor tissue as a novel prognostic marker needs further investigation to inform the selection of combination therapy for these patients.

Several limitations must be acknowledged in our study. First, it was retrospective in nature and involved a relatively small cohort. Additionally, the provision of nivolumab as a second-line treatment was contingent upon the funding conditions specific to our country, potentially affecting generalizability. Moreover, the analysis was conducted using archived tumor tissue; thus, changes in GDF-15 expression after platinum-based therapy could not be assessed, which might influence the results. Despite these limitations, a significant strength of this study is its pioneering exploration of GDF-15 expression levels in relation to immunotherapy response. This research extends beyond NSCLC to include other solid tumors, marking it as the first of its kind. This finding provides valuable insights into the potential role of GDF-15 as a biomarker across a broader spectrum of malignancies.

Although immunotherapy has significantly improved survival rates for patients with advanced NSCLC, a substantial portion of these patients do not benefit from this treatment modality [45, 46]. This study illustrates that tumor GDF-15 expression levels can serve as a predictive marker for both immunotherapy response and overall survival in patients with NSCLC, potentially influencing treatment decisions. Furthermore, there is a critical need to expand upon these findings through prospective trials to further validate the utility of GDF-15 in clinical practice and to enrich the literature.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

GDF-15:

Growth differentiation factor-15

TGF-β:

Transforming growth factor beta

NSCLC:

Non-small cell lung cancer

PFS:

Progression-free survival

OS:

Overall survival

PD-L1:

Programmed death-ligand 1

PD-1:

Programmed death-1

ECOG-PS:

Eastern Cooperative Oncology Group Scale of Performance Status

IHC:

Immunhistochemie

MHC:

Major histocompatibility complex

IL-12:

Interleukin-12

GFRAL:

GDNF family receptor alpha like

RECIST:

Response Evaluation Criteria in Solid Tumors

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Acknowledgements

The present investigation was conducted in accordance with the Project Support initiative of the Turkish Oncology and Immunotherapy Society. The GDF-15 kit only used in the study was provided by our society.

Funding

This research received no external funding.

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Authors and Affiliations

  1. Faculty of Medicine, Department of Medical Oncology, Gazi University, Ankara, Turkey

    Orhun Akdogan, Osman Sutcuoglu, Fatih Gurler, Nuriye Ozdemir, Ahmet Ozet & Ozan Yazici

  2. Faculty of Medicine, Department of Pathology, Gazi University, Ankara, Turkey

    Betul Ogut, Aysenur Sert & Nalan Akyurek

Authors
  1. Orhun Akdogan
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  2. Betul Ogut
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  3. Osman Sutcuoglu
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  4. Aysenur Sert
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  6. Nalan Akyurek
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  7. Nuriye Ozdemir
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  8. Ahmet Ozet
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  9. Ozan Yazici
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Contributions

O.A., O.S. and O.Y. wrote the main manuscript text and A.S. prepared Fig. 1, B.O, A.S. ANDA N.A performed a pathological evaluations, All authors reviewed and approved the manuscript.

Corresponding author

Correspondence to Orhun Akdogan.

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Ethics approval and consent to participate

The study was conducted according to the guidelines of the Declaration of Helsinki. This study was approved by Gazi University Ethics Committee with the approval number E-77082166-604.01.02-763671.

Informed consent

In accordance with local guidelines, the need to obtain informed consent for the use of anonymized retrospective data was waived and approved by the ethics committee.

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The authors declare no competing interests.

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Akdogan, O., Ogut, B., Sutcuoglu, O. et al. The impact of the expression level of growth differentiation factor 15 in tumor tissue on the response to immunotherapy in non-small cell lung cancer. BMC Cancer 24, 954 (2024). https://doi.org/10.1186/s12885-024-12727-3

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  • DOI: https://doi.org/10.1186/s12885-024-12727-3

Keywords

BMC Cancer

ISSN: 1471-2407

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