VDR promotes pancreatic cancer progression in vivo by activating CCL20-mediated M2 polarization of tumor associated macrophage.

BACKGROUND: Activation of VDR pathway was a promising anti-tumor therapy strategy. However, numerous clinical studies have demonstrated the effect of activating VDR is limited, which indicates that VDR plays a complex role in vivos. METHODS: We analyzed the TCGA database to examine the association between VDR expression and immune cell infiltration in pancreatic adenocarcinoma (PAAD). Western blot, ELISA, ChIP, and dual-luciferase reporter assays were performed to determine the mechanism of VDR regulating CCL20. Migration assay and immunofluorescence were used to investigate the role of CCL20 in M2 macrophage polarization and recruitment. We employed multiplexed immunohistochemical staining and mouse models to validate the correlation of VDR on macrophages infiltration in PAAD. Flow cytometry analysis of M2/M1 ratio in subcutaneous graft tumors. RESULTS: VDR is extensively expressed in PAAD, and patients with elevated VDR levels exhibited a significantly reduced overall survival. VDR expression in PAAD tissues was associated with increased M2 macrophages infiltration. PAAD cells overexpressing VDR promote macrophages polarization towards M2 phenotype and recruitment in vitro and vivo. Mechanistically, VDR binds to the CCL20 promoter and up-regulates its transcription. The effects of polarization and recruitment on macrophages can be rescued by blocking CCL20. Finally, the relationship between VDR and M2 macrophages infiltration was evaluated using clinical cohort and subcutaneous graft tumors. A positive correlation was demonstrated between VDR/CCL20/CD163 in PAAD tissues and mouse models. CONCLUSION: High expression of VDR in PAAD promotes M2 macrophage polarization and recruitment through the secretion of CCL20, which activates tumor progression. This finding suggests that the combination of anti-macrophage therapy may improve the efficacy of VDR activation therapy in PAAD.

Predicting postoperative prognosis of pancreatic cancer using a computed tomography-based radio-clinical model: exploring biologic functions.

Computed tomography (CT) imaging has the potential to assist in predicting the prognosis and treatment strategies for pancreatic cancer (PC). This study aimed to develop and validate a radio-clinical model based on preoperative multiphase CT assessments to predict the overall survival (OS) of PC and identify differentially expressed genes associated with OS. METHODS: Patients with PC who had undergone radical pancreatectomy (R0 resection) were divided into development and external validation sets. Independent predictors of OS were identified using Cox regression analyses and included in the nomogram, which was externally validated. The area under the curve was used to measure the model's accuracy in estimating OS probability. RNA sequencing data from The Cancer Genome Atlas were used for gene expression analysis. RESULTS: In the development and external validation sets, survival was estimated respectively for 132 and 27 patients. Multivariate Cox regression analysis identified 5 independent OS predictors: age (P = .049), sex (P = .001), bilirubin level (P = .005), tumor size (P = .020), and venous invasion (P = .041). These variables were incorporated into the nomogram. Patients were divided into high- and low-risk groups for OS and survival curves showed that all patients in the low-risk group had better OS than that of those in the high-risk group (P < .001). Differentially expressed genes in patients with a poor prognosis were involved in neuroactive ligand-receptor interaction. CONCLUSION: The radio-clinical model may be clinically useful for successfully predicting PC prognosis.

Heterogeneous expression of ARID1A in colorectal cancer indicates distinguish immune landscape and efficacy of immunotherapy.

OBJECTIVE: AT-rich interaction domain 1A (ARID1A) mutant tumors show active anti-tumor immune response, which is the potential indication of immunotherapy. However, the relationship between the heterogeneous ARID1A expression and the immune response and immunotherapy efficacy in colorectal cancer (CRC) is still unclear. METHODS: We collected 1113 cases of patients with stage I-IV CRC who underwent primary resection at Harbin Medical University Cancer Hospital. ARID1A expression in CRC tissues was assessed via immunohistochemistry (IHC). CD8, CD163 and FOXP3 were stained by IHC to identify the immune landscape. Clinicopathological features of patients were compared using statistical tests like the Wilcoxon-Mann-Whitney test or χ2 tests. Kaplan-Meier survival analysis with log-rank tests were employed. RESULTS: Heterogeneous ARID1A expression was categorized into integrity expression, complete expression deficiency (cd-ARID1A), partial expression deficiency (pd-ARID1A), and clonal expression deficiency (cld-ARID1A). ARID1A-deficient expression was significant association with dMMR (P value < 0.001). Patients with ARID1A deficiency, compared to ARID1A-proficient patients, exhibited increased infiltration levels of CD8 + P value < 0.0001), CD163 + P value < 0.001), and FOXP3 + P value < 0.001).cells within the tumor tissue. However, in different subgroups, only samples with complete or partial deficiency of ARID1A showed a higher abundance of lymphocyte infiltration. In patients with ARID1A-clonal expression deficiency tumor, the infiltration patterns of three immune cell types were comparable to those in ARID1A-proficient patients. Heterogeneous ARID1A expression is related to the different prognosis and immunotherapythe efficacy in CRC patients. CONCLUSION: Heterogeneous ARID1A expression is accompanied by a different immune landscape. CRC patients with ARID1A-clonal expression deficiency do not benefit from the treatment of immune checkpoint inhibitors (ICIs).

Colorectal medullary carcinoma: a pathological subtype with intense immune response and potential to benefit from immune checkpoint inhibitors.

INTRODUCTION: Different pathological types of colorectal cancer have distinguished immune landscape, and the efficacy of immunotherapy will be completely different. Colorectal medullary carcinoma, accounting for 2.2-3.2%, is characterized by massive lymphocyte infiltration. However, the attention to the immune characteristics of colorectal medullary carcinoma is insufficient. AREA COVERED: We searched the literature about colorectal medullary carcinoma on PubMed through November 2023to investigate the hallmarks of colorectal medullary carcinoma's immune landscape, compare medullary carcinoma originating from different organs and provide theoretical evidence for precise treatment, including applying immunotherapy and BRAF inhibitors. EXPERT OPINION: Colorectal medullary carcinoma is a pathological subtype with intense immune response, with six immune characteristics and has the potential to benefit from immunotherapy. Mismatch repair deficiency, ARID1A missing and BRAF V600E mutation often occurs. IFN-γ pathway is activated and PD-L1 expression is increased. Abundant lymphocyte infiltration performs tumor killing function. In addition, BRAF mutation plays an important role in the occurrence and development, and we can consider the combination of BRAF inhibitors and immunotherapy in patients with BRAF mutant. The exploration of colorectal medullary carcinoma will arouse researchers' attention to the correlation between pathological subtypes and immune response, and promote the process of precise immunotherapy.

Advances and prospects of drug clinical research in colorectal cancer in 2022.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer death worldwide. Clinical research results have provided more treatment opportunities for CRC patients, showing that an optimal combination of existing drugs and new drugs is needed to mitigate the burden of this disease. In this review, we have summarized recent advances in drug clinical research for CRC in 2022, including chemotherapy, targeted therapy, and immunotherapy, to find opportunities for substantial improvements in drug discovery and clinical development methods.

Comparison of the effectiveness of chemotherapy combined with immunotherapy and chemotherapy alone in advanced biliary tract cancer and construction of the nomogram for survival prediction based on the inflammatory index and controlling nutritional status score.

OBJECTIVE: To analyze the effectiveness of combining immune checkpoint inhibitors (ICIs) with first-line therapy in patients with advanced biliary tract cancer (BTC) and explore the biomarkers affecting the prognosis of immunotherapy, to construct a nomogram for the prediction of survival. METHODS: A retrospective study was conducted to include a total of 209 patients with advanced BTC treated in the first line from 2018 to 2022, divided into a combination therapy group (n = 129) and a chemotherapy-only group (n = 80) according to whether ICIs were applied in combination. Univariate and multifactorial COX regression analyses were performed on variables that may affect prognosis to identify independent influences on patient prognosis, and this was used to create nomograms, which were then prospectively validated and calibrated. RESULTS: The median progression-free survival (mPFS) and median overall survival (mOS) of patients in the combination therapy group were higher than those in the chemotherapy alone group [hazard ratio (HR) = 1.152, 95% confidence interval (CI): 0.7848-1.692, p = 0.0004, and HR = 1.067, 95% CI: 0.7474-1.524, p = 0.0016]. The objective response rate (ORR) of patients in the combination therapy and chemotherapy alone groups was 39.5% (51/129) vs. 27.5% (22/80), and the disease control rate (DCR) between the two groups was 89.9% (116/129) vs. 83.8% (67/80). Univariate analysis revealed the gender, presence of long-term tobacco and alcohol, degree of histological differentiation, serum albumin level, presence of liver metastases, presence of multi-visceral metastases, response, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), glycoprotein antigen 19-9 (CA19-9), systemic inflammatory index (SII), and controlling nutritional status (CONUT) scores were statistically significant with patient prognosis (all P values < 0.05). Multi-factor COX regression analysis was continued for the above variables, and the results showed that NLR, MLR, PLR, SII, and CONUT scores were independent influences on patients' OS (all p values < 0.05). A nomogram (C-index 0.77, 95% CI: 0.71-0.84) was created based on these independent influences and later validated using a validation cohort (C-index 0.75, 95% CI: 0.68-0.81). The time-dependent receiver operator characteristic curve (ROC) showed that the area under curve (AUC) of the training cohort patients at 12, 18, and 24 months was 0.72 (95% CI: 0.63-0.81), 0.75 (95% CI: 0.67-0.85), and 0.77 (95% CI: 0.66-0.87) and the AUC of the validation cohort was 0.69 (95% CI: 0.58-0.79), 0.74 (95% CI: 0.65-0.87), and 0.71 (95% CI: 0.64-0.89), respectively. Finally, calibration was performed using calibration curves, and the results showed that nomograms based on inflammatory metrics and CONUT scores could be used to assess survival (12, 18, and 24 months) in patients with advanced BTC treated with ICIs in the first line. CONCLUSION: Patients with advanced BTC benefit more from first-line treatment with standard chemotherapy in combination with ICIs than with chemotherapy alone. In addition, nomograms based on inflammatory metrics and CONUT scores can be used to predict survival at 12, 18, and 24 months in patients with advanced BTC treated with ICIs.

Retrospective study of the combination of TP and PF regimens with or without immune checkpoint inhibitors for the first-line treatment of locally advanced or advanced esophageal squamous cell carcinoma.

Objective: To investigate the efficacy and safety differences between the cisplatin + paclitaxel (TP) and cisplatin + fluorouracil (PF) regimens in combination with or without immune checkpoint inhibitors (ICIs) in advanced esophageal squamous cell carcinoma (ESCC) first-line treatment and prognostic factors. Methods: We selected the medical records of patients with late stage ESCC admitted to the hospital between 2019 and 2021. Based on the first-line treatment regimen, control groups were divided into chemotherapy plus ICIs (n = 243) and non-ICIs (n = 171), 119 (49%) in the TP + ICIs group, 124 (51%) in the PF + ICIs group, 83 (48.5%) in the TP group, and 88 (51.5%) in the PF group in the control group. We analyzed and compared factors related to efficacy, safety, or response to toxicity and prognosis across four subgroups. Results: The overall objective response rate (ORR) and disease control rate (DCR) of the TP plus ICIs group were 42.1% (50/119) and 97.5% (116/119), respectively, which were 6.6% and 7.2% higher than those of the PF plus ICIs group. Patients in the TP combined with ICIs group had higher overall survival (OS) and progression-free survival (PFS) than those in the PF combined with ICIs group [hazard ratio (HR) = 1.702, 95% confidence interval (CI): 0.767-1.499, p = 0.0167 and HR = 1.158, 95% CI: 0.828-1.619, p = 0.0055] ORR and DCR were 15.7% (13/83) and 85.5% (71/83) in the TP chemotherapy alone group, significantly higher than the PF group [13.6% (12/88) and 72.2% (64/88)] (p < 0.05), OS and PFS were also better in patients treated with TP regimen chemotherapy than PF (HR = 1.173, 95% CI: 0.748-1.839, p = 0.0014 and HR = 0.1.245, 95% CI: 0.711-2.183, p = 0.0061). Furthermore, following the combination of TP and PF diets with ICIs, the OS of the patients was higher than that of the group treated with chemotherapy alone (HR = 0.526, 95% CI: 0.348-0.796, p = 0.0023 and HR = 0.781, 95% CI: 0.0.491-1.244, p < 0.001). Regression analysis showed that the neutrophil-to-lymphocyte ratio (NLR), the control nuclear status score (CONUT), and the systematic immune inflammation index (SII) were independent prognostic factors for the efficacy of immunotherapy (p < 0.05). The overall incidence of treatment-associated adverse events (TRAEs) was 79.4% (193/243) and 60.8% (104/171) in the experimental and control groups, respectively, and there was no statistically significant difference in TRAEs between TP + ICIs (80.6%) and PF + ICIs (78.2%) (61.4%) and PF groups (60.2%) (p > 0.05). Overall, 21.0% (51/243) of patients in the experimental group experienced immune-related adverse events (irAEs), and all of these adverse effects were tolerated or remitted following drug treatment without affecting follow-up. Conclusion: The TP regimen was associated with better PFS and OS with or without ICIs. Furthermore, high CONUT scores, high NLR ratios, and high SII were found to be associated with poor prognosis in combination immunotherapy.

China special issue on gastrointestinal tumors-Regulatory-immunoscore-A novel indicator to guide precision adjuvant chemotherapy in colorectal cancer.

Novel biomarkers are essential to improve the treatment efficacy and overall survival of stage II and III colorectal cancer (CRC), allowing for personalized treatment decisions. Here, the densities of CD8+ and FOXP3+ T cells in the tumor and invasive margin were processed by immunohistochemistry and digital pathology to form a scoring system named regulatory-Immunoscore (RIS). Cox proportional hazards regression models were used to determine the risk factors associated with time to recurrence. Harrell's concordance index and the time-dependent area under the curve were used to assess model performance. A total of 1213 stage I-III DNA mismatch repair-proficient colorectal cancer (pMMR CRC) patients were randomly assigned to a training set (n = 642) and a validation set (n = 571). From the Cox multivariable analysis, the association of RIS with survival was independent of patient age, sex and anatomy-based tumor risk parameters (P < .0001). For stage II patients, chemotherapy was significantly associated with better recurrence time in patients with low (95% confidence interval [CI]: 0.11-0.54, P = .001) and intermediate (95% CI = 0.25-0.57, P < .001) RIS values. In stage III patients treated with adjuvant chemotherapy, a treatment duration of 6 or more months was significantly associated with better recurrence time in patients with intermediate RIS values (95% CI = 0.38-0.90, P = .016) when compared with duration under 6 months. Therefore, these findings suggest that RIS is reliable for predicting recurrence risk and treatment responsiveness for patients with stage I-III pMMR CRC.

Epigenetic-related gene mutations serve as potential biomarkers for immune checkpoint inhibitors in microsatellite-stable colorectal cancer.

Background: Combination therapy with immune checkpoint inhibitors (ICIs) may benefit approximately 10-20% of microsatellite-stable colorectal cancer (MSS-CRC) patients. However, there is a lack of optimal biomarkers. This study aims to understand the predictive value of epigenetic-related gene mutations in ICIs therapy in MSS-CRC patients. Methods: We analyzed DNA sequences and gene expression profiles from The Cancer Genome Atlas (TCGA) to examine their immunological features. The Harbin Medical University Cancer Hospital (HMUCH) clinical cohort of MSS-CRC patients was used to validate the efficacy of ICIs in patients with epigenetic-related gene mutations (Epigenetic_Mut). Results: In TCGA, 18.35% of MSS-CRC patients (78/425) had epigenetic-related gene mutations. The Epigenetic_Mut group had a higher tumor mutation burden (TMB) and frameshift mutation (FS_mut) rates. In all MSS-CRC samples, Epigenetic_Mut was elevated in the immune subtype (CMS1) and had a strong correlation with immunological features. Epigenetic_Mut was also associated with favorable clinical outcomes in MSS-CRC patients receiving anti-PD-1-based therapy from the HMUCH cohort. Using immunohistochemistry and flow cytometry, we demonstrated that Epigenetic_Mut samples were associated with increased anti-tumor immune cells both in tumor tissues and peripheral blood. Conclusion: MSS-CRC patients with epigenetic regulation impairment exhibit an immunologically active environment and may be more susceptible to treatment strategies based on ICIs.