Abstract
Purpose
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a 5-year survival low of 2% in advanced cases. Despite being a fatal disease, there is a lack of a good predictor of prognosis which can aid in the management of patients. The tumor microenvironment of PDAC, including immune cells, plays a vital role in the progression and invasiveness of PDAC. Cluster of differentiation 47 (CD47) which has a “don't eat me signal” to macrophages through receptor signal regulatory protein alpha, prevents immune cell surveillance of cancer cells. This contributes to the immune escape and invasiveness of cancer.
Methods
We obtained pancreatic cancer tissue microarray samples from 98 patients treated in Hanyang University Hospital. The diagnosis was proven by a tissue biopsy obtained after surgical resection. Immunohistochemical staining was done using CD47 antibody. Data was analyzed using R software ver. 4.3.3.
Results
In a study of 98 patients with PDAC, CD47 expression (54.1%) was significantly correlated with advanced disease stage. Positive CD47 expression was associated with lower overall survival (P = 0.028) and disease-free survival (P = 0.005) in all patients. In advanced-stage patients, CD47 remained a predictor of lower overall survival (P = 0.012) and disease-free survival (P = 0.023). Multivariate analysis identified positive CD47 expression as an independent factor affecting overall survival (P = 0.048). These results emphasize CD47's prognostic relevance in PDAC, particularly in advanced stages.
Conclusion
Positive CD47 expression in PDAC indicates an advanced stage of the disease and independently predicts poor outcomes. This highlights CD47's role as a crucial prognostic marker in advanced PDAC stages.
Keywords: CD47 antigen, Pancreatic neoplasms, Tumor microenvironment, Prognosis, Tissue array analysis
INTRODUCTION
Pancreatic cancer is among the deadliest solid tumors, ranking as the 12th most common cancer, making up 2.6% of all cancers. Moreover, it contributes to 4.7% of all cancer deaths, making it the 7th leading cause of cancer-related death [1]. Currently, the rising incidence is attributed to 495,773 new cancer cases worldwide in 2020 with an estimated 466,003 deaths [2]. With a prognosis marked by less than 10% overall survival at 5 years, it is anticipated to surpass breast and colorectal cancer, becoming the second leading cause of tumor-related death by 2030 [3]. The challenge lies in the difficulty of early diagnosis and effective treatment. Early diagnosis yields a mere 10% disease-free rate after treatment, emphasizing the urgency for improved diagnostic methods. Unfortunately, over half of patients are diagnosed in advanced stages, where metastasis has already occurred. This contributes to the dismal prognosis and low survival rates. Although surgery stands as the sole curative potential, fewer than 20% of patients present with resectable tumors, emphasizing the pressing need for breakthroughs in early detection and treatment strategies [4].
Although environmental and genetic risk factors have been identified for many cancers, risk factors for pancreatic cancer remain unclear. Therefore, the primary cause of pancreatic cancer remains largely unknown. Although genetic risk factors are hypothesized, the mechanisms behind them are not fully elucidated. Compared with other cancers, pancreatic ductal adenocarcinoma (PDAC) lacks actionable alterations beyond BRAC1, BRAC2, and microsatellite instability-high which are found in very few patients [5]. This complicates the targeting of specific risk factors for therapeutic interventions. Despite this, pancreatic cancer research has seen limited progress compared to other cancer types.
The aggressiveness of pancreatic cancer stems from its intricate tumor microenvironment (TME). Pancreatic cancer is known for its very dense stroma, low number of high-quality neoantigens, and poor T-cell infiltration. This is attributed to the low response to immunotherapy. Reportedly, the downregulation of major histocompatibility complex class I expression limits the occurrence of tumor-specific T cells. Because immune surveillance is not strong, it is attributed to the escape of cancer cells from T-cell-mediated immune recognition, leading to disease progression. Within this dynamic TME, various components, including cancer-supporting fibroblasts, endothelial cells, and immune cells, such as macrophages, contribute to invasiveness, drug resistance, and metastasis [4]. Cross-communication between supporting and cancer cells promotes tumor growth.
Recent investigations emphasize the pivotal role of cluster of differentiation 47 (CD47) expression in both hematologic malignancies and solid tumors [6,7]. CD47 is a transmembrane protein expressed in many cells including cancer cells. It interacts with multiple proteins, including thrombospondin-1, which plays a role in angiogenesis and inflammation. CD47's unique capability to distinguish self from non-self-cells, through the transmembrane receptor SIPRα expressed on macrophages generates the ‘don't eat me’ signal. Targeting this signaling pathway through immunomodulation emerges as a potential avenue for harnessing the body's macrophages to eliminate cancer cells. CD47, identified as a dominant anti-engulfment signal on tumor cells, exhibits overexpression in various cancers. Given its expression across a spectrum of cells, targeting CD47 provides a promising approach not only for addressing cancer-bearing cells but also for modulating the intricate dynamics of the TME [8,9,10].
As evidenced above, rapid and effective diagnosis and treatment of PDAC is urgently needed. A dense TME that is abundant in immune cells can be a target for immunotherapy. CD47 has been studied in multiple malignancies and is effective, especially in patients with hematologic malignancies [11]. It is reported, that blocking the CD47 “don't eat me” signaling has been shown to increase the ability of macrophages to recognize and eliminate PDAC cancer cells. This has been shown to improve the time to progression of metastatic tumors and improve survival in murine models [9,12]. Therefore, we aimed to explore the use of CD47 as a potential diagnostic tool and prognostic marker for PDAC.
We investigated the immunohistochemical expression of CD47 in 98 tumor microarrays (TMA) obtained from patients with PDAC and analyzed the correlation between its expression and various clinicopathologic factors. Additionally, to reveal the prognostic importance of CD47, survival analyses were conducted according to subgroups and advanced PDAC stages.
METHODS
Ethics statements
This study was approved by the Institutional Review Board of Hanyang University Hospital (No. HYUH 2024-07-039). This study was performed in accordance with the Declaration of Helsinki and written informed consent was waived due to its retrospective nature.
Sample preparation
A total of 108 patient samples, spanning 16 years from 2008 to 2023, were obtained from Hanyang University Hospital. TMA slides were prepared, using resected tissue samples from patients with PDAC. Subsequently, 104 out of the 108 cases (96.3%) within the cohort were available for analysis on the TMA sections. Patients lacking sufficient tissue on TMA slides and those with incomplete clinical data were excluded, resulting in the inclusion of 98 patients.
Immunohistochemical study
Immunohistochemical staining targeting CD47 was conducted on 4-µm-thick sections from TMA blocks using the Ventana Benchmark XT automated staining system (Ventana Medical Systems), adhering to the manufacturer's protocol. The anti-CD47 rabbit monoclonal antibody (ab218810, Abcam) was applied at a dilution factor of 1:200. Evaluation of membrane staining in tumor cells was performed using the H-score method. Afterward, the percentage of stained tumor cells was scored based on a 4-tier system (0, negative; 1+, weak; 2+, moderate; and 3+, strong), with the total immunoreactivity score ranging from 0 to 300. The cases were categorized into negative-expression (H-score, <10) and positive-expression groups (H-score, ≥10) [13]. All immunoreactivity assessments were conducted blindly to clinicopathologic factors and patient survival. The H-score was calculated as follows: H-score = 1 × (% of 1+ cells) + 2 × (% of 2+ cells) + 3 × (% of 3+ cells).
Statistical methods
Statistical data analysis was conducted using R software ver. 4.3.3 (The R Foundation). The chi-square test was utilized to investigate the association between candidate CD47 expression and clinicopathological characteristics of patients. To elucidate the prognostic significance of CD47 expression in pancreatic cancer patients, our study focused on overall survival as the primary endpoint. Survival curves were constructed using the Kaplan-Meier method, and differences between survival curves were evaluated using the log-rank test. Overall survival refers to the duration from the diagnosis of the disease until death from any cause, while disease-free survival indicates the period after treatment during which no signs or symptoms of the disease recur. We conducted analyses using both univariate and multivariate Cox regression models to determine the impact of CD47 expression levels on patient outcomes. Only variables showing significant differences in the univariate analysis were included in the multivariate analysis. Statistical significance was determined using 2-tailed tests with a threshold of P < 0.05.
RESULTS
Baseline characteristics of the patients with pancreatic ductal adenocarcinoma
The data from 98 patients diagnosed with PDAC were collected at Hanyang University Hospital. The mean age was 69 years (range, 62–75 years), and there was an equal male-to-female ratio. Seventy-three percent were presented with PDAC American Joint Committee on Cancer (AJCC) stage 2 or higher at diagnosis. Additionally, 2/3 had lymphatic involvement, and 1/3 exhibited vascular invasion. Notably, 88.8% of patients showed perineural invasion and 90.8% of patients had direct invasion into adjacent organs. The majority of PDAC cases (70.4%) involved the head of the pancreas, with 2/3 of patients underwent the Whipple procedure (Table 1). On average, patients survived for 26 months, with an average disease-free survival of 14 months.
Table 1. Clinicopathologic characteristics of patients with pancreatic ductal adenocarcinoma.
Values are presented as number only, median (interquartile range), or number (%).
CD47, cluster of differentiation 47; PPPD, pylorus-preserving pancreaticoduodenectomy.
CD47 expression and correlation with clinicopathologic features
CD47 expression was assessed in 98 PDAC tissues on tumor microarray slides, yielding a mean H-score of 40.8 (range, 0–300). Notably, 54.1% of patients (53 individuals) exhibited positive CD47 expression (Fig. 1, Table 1). Positive CD47 expression was significantly correlated with the AJCC stage (P = 0.043), N-stage (P = 0.05), perineural invasion (P = 0.011), and tumor location (P = 0.005). However, no associations were observed with T-stage, M-stage, marginal involvement, lymphatic invasion, or vascular invasion (Table 2). Subgroup analysis of patients with advanced disease (stages 2 and above) revealed statistically significant associations between positive CD47 expression and AJCC stage (P = 0.016), lymphatic invasion (P = 0.019), and vascular invasion (P = 0.01) (Table 3).
Fig. 1. Immunohistochemical staining of CD47 in pancreatic ductal adenocarcinoma tissues (×400). The intensity of CD47 staining was graded as (A) negative, 0; (B) weak, 1+; (C) moderate, 2+; or (D) strong, 3+. CD47, cluster of differentiation 47.
Table 2. Correlation between CD47 expression and clinicopathologic factors of patients with pancreatic ductal adenocarcinoma.
Values are presented as number (%).
CD47, cluster of differentiation 47; PPPD, pylorus-preserving pancreaticoduodenectomy.
a)Analyzed by Fisher exact test or Pearson chi-square test.
Table 3. Subgroup analysis of CD47 expression in patients with advanced pancreatic ductal adenocarcinoma.
Values are presented as number (%).
CD47, cluster of differentiation 47; PPPD, pylorus-preserving pancreaticoduodenectomy.
a)Analyzed by Fisher exact test or Pearson chi-square test.
Prognostic significance of CD47 expression in patients with pancreatic ductal adenocarcinoma
The impact of CD47 expression on the survival of pancreatic cancer patients was examined. In the entire cohort of 98 patients, those with positive CD47 expression exhibited lower overall survival (P = 0.028) and disease-free survival (P = 0.005) compared to the negative CD47 expression group (Fig. 2C, D).
Fig. 2. Kaplan-Meier survival curves of patients with pancreatic ductal adenocarcinoma stratified based on CD47 expression. (A) Survival curve for the disease stage, (B) survival curve for the lymph node (LN) metastasis, (C) overall survival of patients by CD47 expression, and (D) disease-free survival of patients by CD47 expression. CD47, cluster of differentiation 47.
Subgroup survival analysis for advanced-stage patients indicated that positive CD47 expression was associated with lower overall survival (P = 0.012) and significantly impacted disease-free survival (P = 0.023) compared to the negative CD47 expression group (Fig. 3A, B).
Fig. 3. Kaplan-Meier survival curves of patients with advanced-stage pancreatic ductal adenocarcinoma. (A) Advanced-stage disease patient's overall survival and (B) disease-free survival stratified based on cluster of differentiation 47 (CD47) expression.
Univariate and multivariate analysis of CD47 in patients with pancreatic ductal adenocarcinoma
In the univariate analysis, we observed a compelling association between CD47 expression and overall survival. Elevated CD47 expression levels correlated with a 1.67-fold increased risk of mortality (95% confidence interval [CI], 1.06–2.63; P = 0.027). This finding underscores the potential prognostic utility of CD47 as a biomarker in pancreatic cancer, suggesting its role in influencing disease progression and patient survival outcomes.
Additionally, the disease stage exhibited a significant association with overall survival. Each incremental advancement in the disease stage was associated with a 1.37-fold increase in the hazard of death (95% CI, 1.04–1.79; P = 0.024), highlighting the profound impact of disease extent on patient prognosis.
Subsequent multivariate analysis, which adjusted for potential confounding variables, confirmed the independent prognostic value of CD47 expression. Even after accounting for disease stage and other clinicopathologic factors, elevated CD47 expression levels remained significantly associated with adverse outcomes, with a hazard ratio of 1.66 (95% CI, 1.00–2.74; P = 0.048). This underscores the robustness of CD47 as a prognostic marker in pancreatic cancer, suggesting its potential as a clinically relevant biomarker for risk stratification and treatment decision-making (Table 4).
Table 4. Cox regression analysis of prognostic factors for patients with pancreatic ductal adenocarcinoma.
HR, hazard ratio; CI, confidence interval; CD47, cluster of differentiation 47.
DISCUSSION
Pancreatic cancer stands out as one of the most aggressive diseases, largely because of its propensity for late diagnosis, often resulting from subtle early symptoms [1,14,15]. Consequently, there exists an urgent requirement for dependable predictors that can efficiently categorize patients, facilitating the implementation of more personalized and advanced treatment strategies. In pancreatic cancer, cancer markers like CA19-9 have proven useful in stratifying pancreatic cancer patients with worse disease progression, but less have been done in terms of immune markers [16].
As advancements in cancer treatments progress, pancreatic cancer remains notably challenging to combat, leading to lower survival rates. A significant obstacle contributing to this challenge is the dense desmoplastic microenvironment, which hampers the efficacy of conventional chemoradiotherapies [17,18]. Within this microenvironment, macrophages play a pivotal role in immune surveillance. These macrophages exhibit 2 distinct polarization states: the M1 type, which fosters proinflammatory and antitumoral effects through cytokine secretion and phagocytosis, and the M2 type, which promotes tumor progression by facilitating protumor cytokine production, matrix remodeling, and angiogenesis [6,10,18,19]. The effectiveness of M1-type phagocytosis is compromised when CD47 is highly expressed, as it sends a ‘don't eat me’ signal upon interaction with the signal regulatory protein alpha (SIRPα) receptor on macrophages [6,17]. This interaction ultimately enables cancer cells to evade normal immune surveillance mechanisms. When CD47 binds to SIRPα on macrophages, it initiates a cascade of intracellular signaling that results in the inhibition of phagocytosis. This interaction not only prevents the clearance of cancer cells but also alters the functional state of macrophages. In the presence of high CD47 levels, macrophages may polarize towards the M2 phenotype, which is associated with tumor-promoting activities, such as the secretion of anti-inflammatory cytokines, promoting angiogenesis, and remodeling the extracellular matrix [6].
Additionally, CD47 can interfere with the activation of T cells and other immune cells by modulating the TME. By inhibiting macrophage activation and promoting an immunosuppressive environment, CD47 expression contributes to the overall failure of the immune system to mount an effective response against tumors.
The presence of CD47 protein has been observed across various cancer types and is often associated with poorer survival outcomes in patients [7,9,10,20,21]. Our findings align with existing literature, demonstrating that patients with positive CD47 expression levels tend to have worse prognoses compared to those with negative expression levels. Notably, positive CD47 expression has been linked to lymphatic invasion and vascular involvement, which are characteristic features of advanced disease, as observed in other cancer studies as well [10,20].
Patients exhibiting positive CD47 expression levels often present with advanced stage in multiple cancer types [7,9,10,12,20]. Although surgical resection combined with chemoradiotherapy remains the primary treatment approach for PDAC, progress in incorporating immunotherapeutic strategies such as programmed death-1 (PD-1)/programmed death-ligand (PDL) inhibitors and CD47/SIRPα has been limited compared to other cancer types [10,20,22]. Studies on PDAC and CD47 have shown that higher CD47 expression is associated with lower survival rates and more advanced disease stages. Additionally, CD47 expression correlates with high levels of immune cells expressing markers like CD68 and CD163 [9]. CD47 is particularly interesting because it targets the specific SIRPα–CD47 signaling cascade. Blocking CD47 will selectively affect cells interacting with the SIRP receptor. However, most research on CD47 was conducted using cell lines and murine PDAC models, making it challenging to directly apply the results to human PDAC. Our study, on the other hand, used human tissue samples directly, providing important information relevant to human PDAC.
Immunotherapy has garnered significant attention in recent years, evidenced by notable advancements in cancer treatment. The application of immune checkpoint inhibitors has seen widespread success in metastatic melanoma, renal cell carcinoma, head and neck cancers, and non-small lung cancer [18,21,23]. In the case of pancreatic cancer, no immunotherapy drugs are approved for the treatment. However, multiple clinical trials are ongoing to discover effective immunotherapeutic drugs and tumor vaccines for this aggressive cancer [24,25]. Most of these trials involve combination therapies using 2 or more immune drugs. One such combination under investigation includes anetumab ravtansine which are anti–PD-1 and anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4) agents. This combination is currently in a Phase 1b clinical trial, but it has yet to demonstrate significant effectiveness [26]. Despite these efforts, more research and development are necessary to find effective immunotherapy treatments for PDAC, as the TME plays a crucial role in cancer progression and resistance to therapy.
Clinical trials have shown promising results with anti-CD47 antibodies, especially in hematologic malignancies [27]. Unlike well-studied immune checkpoint proteins like PD-1/PDL-1 and CTLA-4, the CD47/SIPRα pathway represents a relatively new and intriguing area of interest in cancer research. Hu5F9-G4, a humanized anti-CD47 antibody, has demonstrated therapeutic effects in clinical trials for pediatric brain tumors, showing efficacy in both in vivo and in vitro studies with an acceptable safety profile [28]. Another humanized immunoglobulin 2 antibody, AO-176, which also targets CD47, is currently undergoing clinical trials for treating advanced solid tumors, both as a single agent and in combination with paclitaxel [29]. Additionally, magrolimab, another anti-CD47 drug, has been studied in combination with the PD-L1 inhibitor avelumab, showing promising tumor shrinkage effects in ovarian cancer patients [30]. These developments highlight the potential of anti-CD47 therapies in both hematologic and solid tumors. If we can strategically target the CD47 signaling pathway, it presents a potential avenue for augmenting the body's immune response against pancreatic cancer, particularly by leveraging the activity of macrophages.
This evidence highlights the potential of immune checkpoint therapy, prompting the exploration of alternative strategies to target the complex TME. Combination therapies involving immune checkpoint inhibitors alongside conventional chemotherapy hold promise for overcoming therapeutic resistance and improving patient outcomes. As we continue to explore alternative strategies to target the complex TME, the integration of immunotherapeutic interventions represents a promising avenue for enhancing the efficacy of pancreatic cancer treatment regimens [4,9,23].
In conclusion, positive CD47 expression in PDAC is closely associated with advanced disease characteristics and emerges as an independent predictor of unfavorable prognosis. This study underscores the potential of CD47 as a robust prognostic indicator, particularly in the context of advanced stages of PDAC. Targeting CD47 holds promise as a therapeutic strategy to improve patient outcomes, highlighting the need for further investigation in clinical interventions for this challenging malignancy.
Footnotes
Fund/Grant Support: This study was supported by the Research Program of the Korean Association for the Hepato-Biliary-Pancreatic Surgery for 2024 (KAHPBS-24-03).
Conflict of Interest: No potential conflict of interest relevant to this article was reported.
- Conceptualization: All authors.
- Formal Analysi, Investigation, Methodology: EDA, SL.
- Project Administration: DC, HK, JYK.
- Writing – Original Draft: EDA, SL.
- Writing – Review & Editing: All authors.
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