Casp8 acts through A20 to inhibit PD-L1 expression: The mechanism and its implication in immunotherapy.

Immunotherapy targeting the PD-L1/PD-1 pathway is a novel type of clinical cancer treatment, but only small subsets of patients can benefit from it because of multiple factors. PD-L1/PD-1 expression is a biomarker for predicting the efficacy of anti-PD-L1/PD-1 therapy, which highlights the importance of understanding the regulatory mechanisms of PD-L1 expression in cancer cells. Casp8 is an apical caspase protease involved in mediating cell apoptosis, but it also has multiple nonapoptotic functions. Casp8 mutations are associated with increased risks of cancer, and low expression of Casp8 is closely connected with poor prognosis in patients with cancer. In addition, mutations of Casp8 in lymphocytes also lead to human immunodeficiency, thereby causing dysfunction of the innate immune system, but the roles of Casp8 in antitumor immunity remain unclear. Here, we found that knocking down Casp8 in mouse melanoma cells promoted tumor progression in an immune system-dependent manner. Mechanistically, Casp8 induced PD-L1 degradation by upregulating TNFAIP3 (A20) expression, a ubiquitin-editing enzyme that results in PD-L1 ubiquitination. In addition, compared with Casp8fl/fl mice, mice with conditional deletion of Casp8 in natural killer (NK) cells (Ncr1iCre/+ Casp8fl/fl mice) showed a decreased frequency of IFN-γ+ and CD107a+ NK cells but an increased frequency of PD-1+ and CTLA-4+ NK cells. Melanoma cells with Casp8 knocked down exhibited sensitivity to anti-PD-1 or anti-CTLA-4 antibody treatments, particularly in Ncr1iCre/+Casp8fl/fl mice. Together, the results indicate that Casp8 induces PD-L1 degradation by upregulating A20 expression and that decreased Casp8 expression is a potential biomarker for predicting the sensitivity to anti-PD-L1/PD-1 immunotherapy.

Cisplatin/capecitabine with intensity-modulated radiation therapy in anal squamous cell carcinoma: a preliminary study.

OBJECTIVE: Mitomycin (MMC)/5-fluoroural (5-FU) with concurrent radiation is the standard treatment of anal squamous cell carcinoma (ASCC). The aim of this study is to evaluate the efficacy and safety of cisplatin/capecitabine (XP) as an alternative with intensity-modulated radiation therapy (IMRT) in ASCC setting. METHODS: We retrospectively screened all patients with stage I-IV ASCC from January 2010 to June 2019. The records of patients who received definitive chemoradiation with cisplatin/capecitabine (XP) and IMRT were collected and analyzed. RESULTS: The first patient was treated with XP in 2017, so totally 11 patients were included in our study from January 2017 to June 2019. All patients have experienced clinical complete response (cCR). After a median follow-up of 30 months (range, 18-39 months), no patient had local recurrence or distant metastasis. Two-year colostomy-free survival (CFS) and two-year disease-free survival (DFS) were both 100%. The median overall survival (OS) has not reached. Grade 3 acute toxicities included leukopenia (1, 9.1%), neutropenia (2, 18.2%) and thrombocytopenia (2, 18.2%). No grade 4 acute adverse events occurred. CONCLUSION: In our study, cisplatin/capecitabine combined with IMRT was safe in ASCC patients, with favorable efficacy as an alternative, and is expected to be explored in study with larger sample.

Effectiveness of PD-1 inhibitor-based first-line therapy in Chinese patients with metastatic gastric cancer: a retrospective real-world study.

Objective: Programmed cell death protein-1 (PD-1) inhibitor-based therapy has demonstrated promising results in metastatic gastric cancer (MGC). However, the previous researches are mostly clinical trials and have reached various conclusions. Our objective is to investigate the efficacy of PD-1 inhibitor-based treatment as first-line therapy for MGC, utilizing real-world data from China, and further analyze predictive biomarkers for efficacy. Methods: This retrospective study comprised 105 patients diagnosed with MGC who underwent various PD-1 inhibitor-based treatments as first-line therapy at West China Hospital of Sichuan University from January 2018 to December 2022. Patient characteristics, treatment regimens, and tumor responses were extracted. We also conducted univariate and multivariate analyses to assess the relationship between clinical features and treatment outcomes. Additionally, we evaluated the predictive efficacy of several commonly used biomarkers for PD-1 inhibitor treatments. Results: Overall, after 28.0 months of follow-up among the 105 patients included in our study, the objective response rate (ORR) was 30.5%, and the disease control rate (DCR) was 89.5% post-treatment, with two individuals (1.9%) achieving complete response (CR). The median progression-free survival (mPFS) was 9.0 months, and the median overall survival (mOS) was 22.0 months. According to both univariate and multivariate analyses, favorable OS was associated with patients having Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. Additionally, normal baseline levels of carcinoembryonic antigen (CEA), as well as the combination of PD-1 inhibitors with chemotherapy and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive MGC, independently predicted longer PFS and OS. However, microsatellite instability/mismatch repair (MSI/MMR) status and Epstein-Barr virus (EBV) infection status were not significantly correlated with PFS or OS extension. Conclusion: As the first-line treatment, PD-1 inhibitors, either as monotherapy or in combination therapy, are promising to prolong survival for patients with metastatic gastric cancer. Additionally, baseline level of CEA is a potential predictive biomarker for identifying patients mostly responsive to PD-1 inhibitors.

Capecitabine/cisplatin combined with concurrent intensity-modulated radiation therapy: a feasible therapeutic strategy for anal squamous cell carcinoma.

PURPOSE: To evaluate the efficacy and safety of capecitabine/cisplatin (XP) combined with intensity-modulated radiation therapy (IMRT) in patients with non-metastatic anal squamous cell carcinoma (ASCC). METHOD AND MATERIALS: All patients with ASCC who received radical concurrent chemoradiotherapy in the past 8 years were screened. Patients who received XP or mitomycin/5-fluorouracil (MF) were selected and analyzed retrospectively. RESULTS: ASCC is an uncommon cancer, there were 36 patients were included in our study. The XP group and MF group included 18 patients each. The clinical complete response (cCR) rates in the XP group and the MF group were 94.4% and 88.9%, respectively (P = 1). The 2-year local control (LC), disease-free survival (DFS), and colostomy-free survival (CFS) rates were higher in the XP group than in the MF group (100% vs 93.3%, P = 0.32). Hematologic toxicities, especially grade ≥ 3 leukopenia (11.1% vs 44.4%, P = 0.06) and neutropenia (5.6% vs 61.1%, P = 0.001), were lower in the XP group than MF group. As a result of fewer side effects, fewer patients in the XP group demanded the dose reduction of chemotherapy (11.1% vs 50%, P = 0.03) and radiation interruption (55.6% vs 77.8%, P = 0.289). Delayed radiotherapy was shorter in the XP group (2.5 vs 6.5 days, P = 0.042) than in the MF group. CONCLUSION: The XP regimen was as effective as the MF regimen in non-metastatic ASCC. Compared with the standard MF regimen, XP combined with IMRT showed higher treatment completion and lower toxicities. It could be considered a feasible alternative for patients with non-metastatic ASCC.

Favorable response to PD-1 inhibitor plus chemotherapy as first-line treatment for metastatic follicular dendritic cell sarcoma of the spleen: a case report.

Follicular dendritic cell sarcoma (FDCS) is an uncommon low-grade malignant sarcoma. For localized FDCS, surgery is the most commonly recommended therapy option. However, there is no standard treatment protocol for metastatic FDCS. Here, we present a 68-year-old female with primary spleen FDCS who had multiple peritoneal metastases. She was treated with sintilimab (PD-1 inhibitor) plus chemotherapy (epirubicin plus ifosfamide) as first-line treatment achieving partial response (PR) and a relatively long progression-free survival (PFS) of 17 months. This case suggests that PD-1 inhibitor plus chemotherapy as first-line therapy seem to be a promising treatment option for metastatic FDCS.

A SwinTransformer-Based Segmentation Framework With Self-Supervised Strategy for Post-Operative Prostate Cancer Radiotherapy.

Radical prostatectomy (prostate removal) is a standard treatment for clinically localized prostate cancer and is often followed by postoperative radiotherapy. Postoperative radiotherapy requires accurate delineation of the clinical target volume (CTV) and lymph node drainage area (LNA) on computed tomography (CT) images. However, the CTV contour cannot be determined by the simple prostate expansion after resection of the prostate in the CT image. Constrained by this factor, the manual delineation process in postoperative radiotherapy is more time-consuming and challenging than in radical radiotherapy. In addition, CTV and LNA have no boundaries that can be distinguished by pixel values in CT images, and existing automatic segmentation models cannot get satisfactory results. Radiation oncologists generally determine CTV and LNA profiles according to clinical consensus and guidelines regarding surrounding organs at risk (OARs). In this work, we design a cascade segmentation block to explicitly establish correlations between CTV, LNA, and OARs, leveraging OARs features to guide CTV and LNA segmentation. Furthermore, inspired by the success of the self-attention mechanism and self-supervised learning, we adopt SwinTransformer as our backbone and propose a pure SwinTransformer-based segmentation network with self-supervised learning strategies. We performed extensive quantitative and qualitative evaluations of the proposed method. Compared to other competitive segmentation models, our model shows higher dice scores with minor standard deviations, and the detailed visualization results are more consistent with the ground truth. We believe this work can provide a feasible solution to this problem, making the postoperative radiotherapy process more efficient.

Efficacy of lenvatinib plus pembrolizumab in hepatocellular carcinoma with metachronous lung metastasis: a report of two cases.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) and a combination of ICIs with targeted antiangiogenic agents are effective in treatment of advanced hepatocellular carcinoma (HCC). Studies have not explored effective biomarkers for prediction of HCC sensitivity to immunotherapy. CASE DESCRIPTION: The current study explored two consecutive patients with HCC with metachronous lung metastasis who were treated with lenvatinib and pembrolizumab as first-line treatment and third-line treatment, respectively. The two cases showed significant tumor shrinkage and long progression-free survival (>19 months and 12 months, respectively). CONCLUSIONS: The findings of the current study and recently published data indicate lung metastasis as a potential clinical therapeutic indicator for efficacy of immunotherapy against HCC.

Capecitabine/cisplatin combined with concurrent intensity-modulated radiation therapy: a feasible therapeutic strategy for anal squamous cell carcinoma

Purpose To evaluate the efficacy and safety of capecitabine/cisplatin (XP) combined with intensity-modulated radiation therapy (IMRT) in patients with non-metastatic anal squamous cell carcinoma (ASCC). Method and materials All patients with ASCC who received radical concurrent chemoradiotherapy in the past 8 years were screened. Patients who received XP or mitomycin/5-fluorouracil (MF) were selected and analyzed retrospectively. Results ASCC is an uncommon cancer, there were 36 patients were included in our study. The XP group and MF group included 18 patients each. The clinical complete response (cCR) rates in the XP group and the MF group were 94.4% and 88.9%, respectively (P = 1). The 2-year local control (LC), disease-free survival (DFS), and colostomy-free survival (CFS) rates were higher in the XP group than in the MF group (100% vs 93.3%, P = 0.32). Hematologic toxicities, especially grade ≥ 3 leukopenia (11.1% vs 44.4%, P = 0.06) and neutropenia (5.6% vs 61.1%, P = 0.001), were lower in the XP group than MF group. As a result of fewer side effects, fewer patients in the XP group demanded the dose reduction of chemotherapy (11.1% vs 50%, P = 0.03) and radiation interruption (55.6% vs 77.8%, P = 0.289). Delayed radiotherapy was shorter in the XP group (2.5 vs 6.5 days, P = 0.042) than in the MF group. Conclusion The XP regimen was as effective as the MF regimen in non-metastatic ASCC. Compared with the standard MF regimen, XP combined with IMRT showed higher treatment completion and lower toxicities. It could be considered a feasible alternative for patients with non-metastatic ASCC (AU)

TLR3 activation efficiency by high or low molecular mass poly I:C.

Toll-like receptor 3 (TLR3) plays a critical role in initiating type I IFN-mediated innate immunity against viral infections. TLR3 recognizes various forms of double stranded (ds) RNA, including viral dsRNA and a synthetic mimic of dsRNA, poly I:C, which has been used extensively as a TLR3 ligand to induce antiviral immunity. The activation efficiency of TLR3 by poly I:C is influenced by various factors, including size of the ligands, delivery methods and cell types. In this study, we examined the stimulatory effect of two commercially-available poly I:Cs [high molecular mass (HMM) and low molecular mass (LMM)] on TLR3 activation in various human cell types by determining the induction of type I and type III IFNs, as well as the antiviral effect. We demonstrated that the direct addition of both HMM- and LMM-poly I:C to the cultures of primary macrophages or a neuroplastoma cell line could activate TLR3. However, the transfection of poly I:C was necessary to induce TLR3 activation in other cell types studied. In all the cell lines tested, the efficiency of TLR3 activation by HMM-poly I:C was significantly higher than that by LMM-poly I:C. These observations indicate the importance and necessity of developing effective TLR3 ligands for antiviral therapy.