The circulating soluble form of the CD40 costimulatory immune checkpoint receptor and liver metastasis risk in rectal cancer

Meltzer, Sebastian; Torgunrud, Annette; Abrahamsson, Hanna; Solbakken, Arne M.; Flatmark, Kjersti; Dueland, Svein; Bakke, Kine Mari; Bousquet, Paula A.; Negård, Anne; Johansen, Christin; Lyckander, Lars Gustav; Larsen, Finn Ole; Schou, Jesper Sølver; Redalen, Kathrine Røe; Ree, Anne Hansen

doi:10.1038/s41416-021-01377-y

Cited by 9 publications

(6 citation statements)

References 61 publications

(65 reference statements)

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“…This highlights a potential diagnostic value of sTIM-3, which we also found to be increased in the serum of PDAC patients. sCD40 was elevated and associated with poor prognosis in multiple myeloma and acute myeloid leukemia 44 , 45 . Our results uncovered a significant prognostic role of sCD40 in PDAC.…”

Section: Discussionmentioning

confidence: 99%

Serum immune checkpoint profiling identifies soluble CD40 as a biomarker for pancreatic cancer

Digomann,

Heiduk,

Reiche

et al. 2023

npj Precis. Onc.

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Pancreatic ductal adenocarcinoma (PDAC) responds poorly to systemic treatment, including new immunotherapeutic approaches. Biomarkers are urgently needed for early disease detection, patient stratification for treatment, and response prediction. The role of soluble CD40 (sCD40) is unknown in PDAC. In this study, we performed a quantitative multiplex analysis of 17 immune checkpoint proteins in serum samples from patients with various stages of PDAC in a discovery study (n = 107) and analyzed sCD40 by ELISA in a validation study (n = 317). Youden’s J statistic was used for diagnostic cut-off optimization. A Cox proportional hazards regression model was applied in an empiric approach for prognostic threshold optimization. Kaplan–Meier estimator and multivariable Cox regression analyses were used for survival analysis. sCD40 was significantly increased in the serum of patients with PDAC compared to healthy cohorts and patients with IPMN. In the validation cohort, the area under the receiver operating characteristic (ROC) c-statistic was 0.8, and combining sCD40 with CA19-9 yielded a c-statistic of 0.95. sCD40 levels were independent of the tumor stage. However, patients who received neoadjuvant chemotherapy had significantly lower sCD40 levels than those who underwent upfront surgery. Patients with a sCD40 level above the empirical threshold of 0.83 ng/ml had a significantly reduced overall survival with a hazard ratio of 1.4. This observation was pronounced in patients after neoadjuvant chemotherapy. Collectively, soluble CD40 may be considered as both a diagnostic and prognostic non-invasive biomarker in PDAC.

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Section: Discussionmentioning

confidence: 99%

Serum immune checkpoint profiling identifies soluble CD40 as a biomarker for pancreatic cancer

Digomann,

Heiduk,

Reiche

et al. 2023

npj Precis. Onc.

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“…In recent years, more and more attention has been paid to RCLM, but most of them have been conducted on the molecular level and radiomics rather than clinicopathological features. Circulating sCD40 (27),Circulating exosomal miR-141-3p and miR-375 (28), CD73 (29), the miR-329-3p/Netrin-1-CD146 Complex (30) have been confirmed to be related to liver metastasis of rectal cancer, and can be used for early prediction of liver metastasis, thereby greatly improving the survival rate of rectal cancer patients. In terms of radiomics, many study also indicated that radiomics based on primary rectal cancer could provide a non-invasive way to predict the risk of rectal cancer with liver metastasis in clinical practice, such as radiomics obtained from MRI (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

Establishment and validation of diagnostic and prognostic prediction models for liver metastasis in patients with rectal cancer: a SEER based study.

Wang,

Zheng,

Chen

2024

Preprint

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Rectal cancer is one of the most common gastrointestinal tumors, among which the liver is the most common site of distant metastasis and liver metastasis leads to poor prognosis. We aimed to develop and validate a diagnostic nomogram to predict the occurrence of rectal cancer with liver metastasis (RCLM) and a prognostic nomogram to predict the cancer-specific survival (CSS) in RCML patients. Data on patients with rectal cancer diagnosed between 2010 and 2013 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate logistic regression, the area under receiver operating characteristic curve (AUC), and multivariate logistic regression were used to determine the independent risk factors of RCLM. Univariate Cox proportional hazards regression and multivariate Cox proportional hazards regression were used to identify independent prognostic factors for RCLM. We then developed two novel nomograms, and the results were evaluated by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). A total of 29367 patients with rectal cancer were included, with an average age of 66.71 ± 12.47 years old. Among them, 3403 patients (11.59%) had liver metastases at the time of diagnosis. The independent risk factors of RCLM included AJCC N, chemotherapy, CEA, DX-lung (Distant metastasis to the lung) and surgical sites. Age, chemotherapy, total number (from the primary tumors), surgery sites, histological type were independent prognostic factors of patients with RCLM. The results of ROC curves, calibration curves, DCA, C-indexes and Kaplan–Meier (K-M) survival curves in the development, validation and testing sets confirmed that two nomograms can precisely predict occurrence and prognosis of RCLM. Two nomograms are expected to be effective tools for predicting the risk of liver metastasis for patients with rectal cancer and personalized prognosis prediction for patients with RCLM, which may benefit clinical decision-making.

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“… 5 , 6 Multiple studies have demonstrated that serum CD40 (sCD40) levels are significantly elevated in patients with HBV infection in comparison to healthy individuals. 7 – 9 Additionally, in patients with chronic hepatitis B (CHB), sCD40 levels are positively correlated with serum alanine aminotransferase and aspartate aminotransferase levels, implying that sCD40 is linked to the severity of liver inflammation. Recent research has identified single-nucleotide polymorphisms (SNPs) in CD40’s Kozak sequence that may affect the start of transcription, and studies have also suggested that SNPs in CD40 are closely linked to autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

A genetic variant in the CD40 gene is related to HBV infection in the Chinese Han population

Wu,

Xu,

Zeng

et al. 2023

Hepatology Communications

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Background: CD40 is an important immune costimulatory molecule that has recently been found to be associated with chronic hepatitis B. This study aims to explore the association between CD40 polymorphisms and HBV infection, as well as to investigate the impact of different rs1883832 genotypes on CD40 expression and its effect on the progression of chronic HBV infection. Methods: We genotyped rs1883832 in 3433 individuals using MassARRAY, and quantified the CD40 expression, including CD40 mRNA, sCD40, and mCD40. The CD40 and HBV infection indicators were assessed to investigate the potential function of rs1883832 in suppressing HBV replication in HepG2.2.15 and HepAD38, CD40L in cytotoxic t lymphocytes (CTLs) and interferon-γ, TNF-α, granzyme B, and perforin were measured to elucidate the mechanism by which CD40 inhibits HBV replication. Results: Our study revealed that the frequencies of CC genotype and C allele of rs1883832 were significantly higher in immune recovery compared to chronic hepatitis B. Individuals with CC genotype exhibited significantly elevated CD40 in serum and B cells compared to TT genotypes in chronic hepatitis B. Additionally, CD40 is capable of inhibiting HBV replication and transcription in hepatocytes by means of interaction with CD40L. A significant negative correlation was found between HBV DNA, HBeAg, and mCD40. Conversely, the expressions of ALT and mCD40 showed a positive correlation, which aligns with the trend of CD40L. Conclusions: rs1883832 C allele may have a protective role in HBV immune recovery. This protective effect could potentially be attributed to the regulation of CD40 expression. The activation of the anti-HBV immune response, which occurs through binding CD40L on CTL, can suppress HBV DNA replication and potentially facilitate immune recovery in HBV infection.

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The circulating soluble form of the CD40 costimulatory immune checkpoint receptor and liver metastasis risk in rectal cancer

Cited by 9 publications

References 61 publications

Serum immune checkpoint profiling identifies soluble CD40 as a biomarker for pancreatic cancer

Serum immune checkpoint profiling identifies soluble CD40 as a biomarker for pancreatic cancer

Establishment and validation of diagnostic and prognostic prediction models for liver metastasis in patients with rectal cancer: a SEER based study.

A genetic variant in the CD40 gene is related to HBV infection in the Chinese Han population

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