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Abstract Background Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC. Methods We assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment. Results HRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8+ T cells, and cytotoxic CD8+ T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8+ T cell penetration and efficacy, overcoming resistance to ICB therapy. Conclusions HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy.

Abstract Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/CCDH1) prevents cell-cycle entry by targeting crucial mitotic proteins for degradation. Phosphorylation of its co-activator CDH1 modulates the E3 ligase activity, but little is known about its regulation after phosphorylation and how to effectively harness APC/CCDH1 activity to treat cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)-catalyzed phosphorylation-dependent cis-trans prolyl isomerization drives tumor malignancy. However, the mechanisms controlling its protein turnover remain elusive. Through proteomic screens and structural characterizations, we identify a reciprocal antagonism of PIN1-APC/CCDH1 mediated by domain-oriented phosphorylation-dependent dual interactions as a fundamental mechanism governing mitotic protein stability and cell-cycle entry. Remarkably, combined PIN1 and cyclin-dependent protein kinases (CDKs) inhibition creates a positive feedback loop of PIN1 inhibition and APC/CCDH1 activation to irreversibly degrade PIN1 and other crucial mitotic proteins, which force permanent cell-cycle exit and trigger anti-tumor immunity, translating into synergistic efficacy against triple-negative breast cancer.

Abstract Background Frailty has been globally recognized as a predictor of adverse postoperative outcomes. Frailty assessment using the five-factor modified frailty index (5-mFI) has recently gained traction; however, long-term outcomes are unknown in colorectal cancer (CRC) surgery. This study aimed to investigate whether the 5-mFI predicted long-term survival and cause of death on the basis of frailty severity in elderly patients who underwent CRC surgery and to determine the risk factors for mortality. Methods A total of 299 patients underwent CRC surgery with curative intent between January 2013 and December 2017. Patients were divided into three groups by the 5-mFI score: group 1 (5-mFI: 0 or 1; n = 164): no frailty; group 2 (5-mFI: 2; n = 91): moderate frailty; and group 3 (5-mFI: ≥ 3; n = 44): severe frailty. Clinicopathological variables, namely comorbidities, 5-mFI, prognostic nutrition index, operative/postoperative data, and outcome, including cause of death, were compared between the three groups. To identify factors associated with death from CRC- and non-CRC-related causes, univariate and multivariate analyses using a Cox regression model were performed. Results The immediate postoperative morbidity of patients with Clavien–Dindo grade ≥ III complications (9.1%) in group 3 was not significantly different from that in group 1 (9.1%) or group 2 (14.3%); however, the 30-day mortality rate (4.5%) in group 3 was significantly higher. Long-term disease-free survival was similar between frailty groups, suggesting that CRC surgery provides oncological benefit to patients irrespective of frailty. The 5-year survival rates in groups 1, 2, and 3 were 83.5%, 71.2%, and 47.9%, respectively, showing a significantly lower survival rate as frailty advanced. Sixty percent of the deaths in frail patients were due to respiratory failure and cardiovascular diseases. Multivariate analysis demonstrated that advanced age, higher 5-mFI score, and longer postoperative hospital stay were risk factors for mortality unrelated to CRC. Multivariate analysis also revealed that advanced tumor stage, carcinoembryonic antigen ≥ 5 ng/ml, undifferentiated tumor, and R1 resection were risk factors for CRC-related mortality. Conclusions The 5-mFI score can predict postoperative short- and long-term outcomes and risk factors for mortality unrelated to CRC. Additionally, long-term survival was negatively associated with the 5-mFI score.

Background: Invasive carcinoma or dysplasia (biliary intraepithelial neoplasia [BilIN]) is often found in the surgical stumps of biliary tract cancer. We investigated whether the presence of BilIN at the surgical margin is a risk factor for recurrence. Materials andMethods: Seventy-five consecutive patients who underwent curative resection for biliary tract cancer were included in this study. We retrospectively evaluated the surgicalmargin status (negative, BilIN, or positive) and analyzed the postoperative disease recurrence rate and recurrence pattern by the status. Results: The disease-free survival rate was significantly worse in the positive margin group than in the negative margin group (11 vs 18months, P = 0.027). There were no statistical differences between the BilIN-positive group and the other two groups. In themultivariate analysis, infiltrative growth c (hazard ratio [HR], 3.348; 95% confidence interval [CI], 1.368-8.195; P = 0.008) and pathological exhumed margin (HR, 2.670; 95%CI, 1.097-6.495; P = 0.030) were independent recurrence factors. Themargin status of BilIN was not associated with recurrence (HR, 0.867; 95% CI, 0.491-2.946; P = 0.687). Conclusions: The BilIN component at the surgical margin was not associated with short-term recurrence, but the pathological exhumed margin positive and infiltrative growth c were. Infiltrative growth c may be a potential predictive factor for recurrence. [ABSTRACT FROM AUTHOR]