Background: Depression is a common, easily ignored, accompanied disease of gastric cancer (GC) patients and is often observed with elevated plasma catecholamine levels. Depression frequently promotes GC progression and leads to poor clinical outcomes; however, the molecular mechanisms underlying depression‐induced GC progression remain poorly understood. We aimed to study the effects of depression on GC progression and explore possible mechanisms mediating the action of depression‐associated catecholamines on GC. Methods: Depression states of GC patients were graded using the Patient Health Questionnaire‐9, and plasma catecholamine levels were examined by high performance liquid chromatography coupled with tandem mass spectrometry. Migrative and invasive GC cells were examined using transwell assays, and metastatic GC niches were imaged using bioluminescence technology in a depression mouse model established with chronic unpredictable mild stress. Mouse depression‐like behaviors were assessed through sucrose preference, forced swimming, and tail suspension tests. Characteristics of the neuroendocrine phenotype were observed via RT‐PCR, Western blotting, flow cytometry, and transmission electron microscopy. Results: Fifty‐one GC patients (age: 53.61 ± 1.79 years; cancer duration: 3.71 ± 0.33 months; depression duration: 2.37 ± 0.38 months; male‐to‐female ratio: 1.55:1) were enrolled in the study. Depression grade was significantly higher in GC patients showing higher plasma levels of catecholamines (epinephrine: P = 0.018; noradrenaline: P = 0.009), higher oncogene metastasis‐associated in colon cancer‐1 (MACC1) level ( P = 0.018), and metastasis ( P < 0.001). Further, depression‐associated catecholamine specifically bound to the beta‐2 adrenergic receptor (β ₂ ‐AR) and upregulated MACC1 expression, and thus promoting neuroendocrine phenotypic transformation through direct binding between MACC1 and synaptophysin. Eventually, the neuroendocrine phenotypic transformation accelerated GC invasion in vitro and metastasis in vivo. However, β ₂ ‐AR antagonist ICI‐118,551 or MACC1 silencing effectively blocked the catecholamine‐induced neuroendocrine phenotypic transformation and eliminated depression‐enhanced GC migration and invasion. Moreover, β ₂ ‐AR blocking or MACC1 silencing prevented GC metastasis attributed to a neuroendocrine phenotype in a depression mouse model. Conclusions: Catecholamine‐induced neuroendocrine phenotypes of GC cells led to depression‐accelerated GC invasion and metastasis via the β ₂ ‐AR/MACC1 axis, while β ₂ ‐AR antagonist or MACC1 silencing could reverse it, showing promising potential therapeutic strategies for improving the outcome of GC patients with comorbid depression.

Intrahepatic cholangiocarcinoma (ICC) is a relatively rare but highly aggressive tumor type that responds poorly to chemotherapy and immunotherapy. Comprehensive molecular characterization of ICC is essential for the development of novel therapeutics. Here, we constructed two independent cohorts from two clinic centers. A comprehensive multiomics analysis of ICC via proteomic, whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-seq) was performed. Novel ICC tumor subtypes were derived in the training cohort (n = 110) using proteomic signatures and their associated activated pathways, which were further validated in a validation cohort (n = 41). Three molecular subtypes, chromatin remodeling, metabolism, and chronic inflammation, with distinct prognoses in ICC were identified. The chronic inflammation subtype was associated with a poor prognosis. Our random forest algorithm revealed that mutation of lysine methyltransferase 2D (KMT2D) frequently occurred in the metabolism subtype and was associated with lower inflammatory activity. scRNA-seq further identified an APOE+C1QB+ macrophage subtype, which showed the capacity to reshape the chronic inflammation subtype and contribute to a poor prognosis in ICC. Altogether, with single-cell transcriptome-assisted multiomics analysis, we identified novel molecular subtypes of ICC and validated APOE+C1QB+ tumor-associated macrophages as potential immunotherapy targets against ICC.

Background: There is no study accessible now assessing the prognostic aspect of radiomics for anti-PD-1 therapy for patients with HCC. Aim: The aim of this study was to develop and validate a radiomics nomogram by incorporating the pretreatment contrast-enhanced Computed tomography (CT) images and clinical risk factors to estimate the anti-PD-1 treatment efficacy in Hepatocellular Carcinoma (HCC) patients. Methods: A total of 58 patients with advanced HCC who were refractory to the standard first-line of therapy, and received PD-1 inhibitor treatment with Toripalimab, Camrelizumab, or Sintilimab from 1st January 2019 to 31 July 2020 were enrolled and divided into two sets randomly: training set (n = 40) and validation set (n = 18). Radiomics features were extracted from non-enhanced and contrast-enhanced CT scans and selected by using the least absolute shrinkage and selection operator (LASSO) method. Finally, a radiomics nomogram was developed based on by univariate and multivariate logistic regression analysis. The performance of the nomogram was evaluated by discrimination, calibration, and clinical utility. Results: Eight radiomics features from the whole tumor and peritumoral regions were selected and comprised of the Fusion Radiomics score. Together with two clinical factors (tumor embolus and ALBI grade), a radiomics nomogram was developed with an area under the curve (AUC) of 0.894 (95% CI, 0.797–0.991) and 0.883 (95% CI, 0.716–0.998) in the training and validation cohort, respectively. The calibration curve and decision curve analysis (DCA) confirmed that nomogram had good consistency and clinical usefulness. Conclusions: This study has developed and validated a radiomics nomogram by incorporating the pretreatment CECT images and clinical factors to predict the anti-PD-1 treatment efficacy in patients with advanced HCC.

Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma (HCC) are urgently needed. The common cytokine receptor γ chain (γ_c) family cytokines such as IL-2, IL-7, IL-15 and IL-21 play fundamental roles in T cell development, differentiation and effector phases. This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy. The antitumor function of AFP-specific T cell receptor-engineered T cells (TCR-T) was augmented by exogenous IL-21 in vitro and in vivo. IL-21 enhanced proliferation capacity, promoted memory differentiation, downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation. A novel engineered IL-21 receptor was established, and TCR-T armed with the novel engineered IL-21 receptors (IL-21R-TCR-T) showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand. IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo. IL-21R-TCR-T exhibited a less differentiated, exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation. The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization. The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.

Introduction: Previous trials demonstrated that anti-angiogenesis or anti-programmed death protein 1 (PD-1) monotherapy showed unsatisfied effect in advanced hepatocellular carcinoma (HCC). No study existed that focus on the effects of camrelizumab and apatinib (“C+A”) combination therapy for HCC patients with the location and extent of portal vein tumor thrombus (PVTT) as the main variable being assessed. This study was to compare the efficacy and tolerability of “C+A” for HCC patients with PVTT. Methods: We retrospectively analyzed patients with advanced HCC and PVTT who underwent “C+A” therapy in a multicenter retrospective cohort from Jan 2019 to July 2020. Outcomes of patients who underwent “C+A” were analyzed by using the Kaplan–Meier method according to types of PVTT: PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C). Results: Sixty-three patients were finally included and the mean duration of follow-up was 12.6 ± 4.5 months. The objective response rate (ORR) and disease control rate (DCR) for the whole cohort were 44.0% and 75.0%, respectively. The median overall survival (OS), progression-free survival (PFS) and time to progression (TTP) were 14.8 months, 11.8 months and not yet reached (NR), respectively. Patients with type B (OS, 15.9 months; PFS, 14.0 months; TTP, NR) or type C (OS, 16.0 months; PFS, 14.9 months; NR) PVTT appear to have better survival benefits compared with type A (OS, 5.8 months; PFS, 5.0 months; TTP, 7.0 months). Along with AFP, the absence of main PVTT was an independent predictive factor for survival at uni- and multivariate analysis. Conclusion: Camrelizumab and apatinib yielded a promising outcome in patients with advanced HCC who developed a tumor thrombus in the first lower-order portal vein branches and was generally safe and had manageable side effects.

Background: Combining an antiangiogenic agent with an anti-PD-1 agent is a promising strategy for unresectable hepatocellular carcinoma (HCC). Aims: To explore the effectiveness and tolerability of lenvatinib plus camrelizumab vs. lenvatinib monotherapy as a first-line treatment for unresectable HCC. Methods: This multicenter, retrospective cohort study included patients with unresectable HCC treated with oral lenvatinib 8 mg daily and intravenous camrelizumab 200 mg every 3 weeks (L+C group) or lenvatinib 12 mg or 8 mg daily (L group) in four Chinese centers between September 2018 and February 2020. Tumor response was evaluated according to RECIST 1.1 and mRECIST. The outcomes included objective response rate (ORR), overall survival (OS), 1-year OS rate, progression-free survival (PFS), and safety. Results: By March 31, 2021, 92 patients were finally included, with 48 and 44 in the L+C and L groups, respectively. ORR was significantly higher in the L+C group than in the L group (RECIST 1.1: 37.5% vs. 13.6%, P=0.009; mRECIST: 41.7% vs. 20.5%, P=0.029). Median OS and 95% confidence interval (CI) was 13.9 (13.3-18.3) months in the L group and not reached in the L+C group (P=0.015). The 1-year survival rate was 79.2% and 56.8% in the L+C and L groups, respectively. Median PFS was 10.3 (6.6-14.0) months and 7.5 (5.7-9.3) months in the L+C and L groups, respectively (P=0.0098). Combined therapy vs. monotherapy was independently associated with a prolonged OS (hazard ratio=0.380, 95% CI=: 0.196-0.739, P=0.004) and a prolonged PFS (hazard ratio=0.454, 95%CI=0.282-0.731, P=0.001). The safety profile was comparable between the two groups. The most common adverse event in the L+C and L groups was loss of appetite (41.7% vs. 40.9%, P=0.941). Three patients in the L+C group and two in the L group terminated treatment owing to adverse events. Conclusion: First-line lenvatinib plus camrelizumab showed better effectiveness than lenvatinib alone in patients with unresectable HCC.