UNASSIGNED: Dysregulation of long noncoding RNAs (lncRNAs) has been reported to be associated with multiple tumors where they act as tumor suppressors or accelerators. The lncRNA CYTOR was identified as an oncogene involved in many cancers, such as gastric cancer, colorectal cancer, hepatocellular carcinoma, and renal cell carcinoma. However, the role of CYTOR in bladder cancer (BCa) has rarely been reported.
UNASSIGNED: Using cancer datasets from The Cancer Genome Atlas (TCGA) program, we analyzed the association between CYTOR expression and prognostic value, oncogenic pathways, antitumor immunity and immunotherapy response in BCa. The influence of CYTOR on the immune infiltration pattern in the urothelial carcinoma microenvironment was further verified in our dataset. Single-cell analysis revealed the role of CYTOR in the tumor microenvironment (TME) of BCa. Finally, we evaluated the expression of CYTOR in BCa in the Peking University First Hospital (PKU-BCa) dataset and its correlation with the malignant phenotype of BCa in vitro and in vivo.
UNASSIGNED: The results indicated that CYTOR was highly expressed in multiple cancer samples, including BCa, and increased CYTOR expression contributed to poor overall survival (OS). Additionally, elevated CYTOR expression was significantly correlated with clinicopathological features of BCa, such as female sex, advanced TNM stage, high histological grade and non-papillary subtype. Functional characterization revealed that CYTOR may be involved in immune-related pathways and the epithelial mesenchymal transformation (EMT) process. Moreover, CYTOR had a significant association with infiltrating immune cells, including M2 macrophages and regulatory T cells (Tregs). CYTOR facilitates the crosstalk between cancer-associated fibroblasts (CAFs) and macrophages, and mediates M2 polarization of macrophages. Correlation analysis revealed a positive correlation between CYTOR expression and programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1)/expression and other targets for specific immunotherapy in BCa, which are recognized to predict the efficacy of immunotherapy.
UNASSIGNED: These results suggest that CYTOR serves as a potential biomarker for predicting survival outcome, TME cell infiltration characteristics and immunotherapy response in BCa.

UNASSIGNED: Aortic stenosis (AS) is a disease characterized by narrowing of the aortic valve (AV) orifice. In relation to this disease, the purpose of this study was to elucidate the relationships among factors such as expression of programmed cell death-1 ligand (PD-L1, which is the ligand of PD-1 protein; together, they play a central role in the inhibition of T lymphocyte function), clinicopathologic characteristics, infiltrating immune cells, and disease severity.
UNASSIGNED: We performed immunohistochemical analysis on the surgically-resected AVs of 53 patients with AS. We used the resultant data to identify relationships among PD-L1 expression, disease severity, and the infiltration of immune cells including cluster of differentiation (CD8)-positive T lymphocytes, cluster of differentiation 163 (CD163)-positive macrophages, and forkhead box protein 3 (FOXP3)-positive regulatory T lymphocytes (Tregs).
UNASSIGNED: PD-L1 expression in resected AVs was significantly associated with being nonsmoker, valve calcification, and the infiltration of CD8-positive T cells and CD163-positive macrophages. Disease severity and valve calcification were significantly associated with low infiltration of FOXP3-positive Tregs and high infiltration of CD8-positive T cells and CD163-positive macrophages. Moreover, calcified AVs with high PD-L1 expression showed active inflammation without FOXP3-positive Tregs but with high levels of CD8-positive T lymphocytes and CD163-positive macrophages.
UNASSIGNED: Immune cell infiltration in the AVs and expression of the immune checkpoint protein PD-L1 were associated with the calcification of AS and disease severity.

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.

UNASSIGNED: Inhibition of the programmed death ligand 1, programmed death 1 pathway has been successfully used for treatment of multiple advanced adult cancers. However, its use in pediatric osteosarcoma is still in its infancy. In this study, we investigated programmed death ligand 1 and other checkpoint molecules\' expression to determine the potential usefulness as targets for drug therapy.
UNASSIGNED: We incubated human wild-type osteosarcoma cells with incremental concentrations of doxorubicin to create a doxorubicin-resistant cell line. Matrigel in vitro invasion assays were used to compare invasiveness. Comparative programmed death ligand 1 expression was evaluated by Western blot assays. An immuno-oncology checkpoint protein panel was used to compare concentrations of 16 other checkpoint molecules. Chi-square tests and Wilcoxon rank-sum tests were used to determine significant differences.
UNASSIGNED: A doxorubicin-resistant cell line was successfully created and was significantly more invasive than wild-type cells (0.47 vs 0.07, P < .001). On Western blot assay, doxorubicin-resistant but not wild-type cells expressed programmed death ligand 1. Doxorubicin-resistant cells had significantly higher levels of T-cell immunoglobulin-3 and cluster of differentiation 86 and higher cluster of differentiation 27, cluster of differentiation 40, lymphocyte-activation gene-3, cluster of differentiation 80, programmed death ligand 1, programmed death ligand 2, and inducible T-cell costimulatory expression than wild-type cells. Both lines expressed B- and T-lymphocyte attenuator, cluster of differentiation 28, herpesvirus entry mediator, and programmed death 1. Herpesvirus entry mediator, cluster of differentiation 40, and programmed death ligand 2 were also present in the culture media of both cell lines.
UNASSIGNED: Doxorubicin-resistant osteosarcoma seems to express higher programmed death ligand 1 than nonresistant wild-type cells. Benchmarking checkpoint molecules may provide the basis for future studies that elucidate pathways of drug resistance and tumor metastasis, biomarkers for cancer prognosis or recurrence, and future targets for directed drug therapy.

T cells are critical to fight pathogenic microbes and combat malignantly transformed cells in the fight against cancer. To exert their effector function, T cells produce effector molecules, such as the pro-inflammatory cytokines IFN-γ, TNF-α and IL-2. Tumors possess many inhibitory mechanisms that dampen T cell effector function, limiting the secretion of cytotoxic molecules. As a result, the control and elimination of tumors is impaired. Through recent advances in genomic editing, T cells can now be successfully modified via CRISPR/Cas9 technology. For instance, engaging (post-)transcriptional mechanisms to enhance T cell cytokine production, the retargeting of T cell antigen specificity or rendering T cells refractive to inhibitory receptor signaling can augment T cell effector function. Therefore, CRISPR/Cas9-mediated genome editing might provide novel strategies for cancer immunotherapy. Recently, the first-in-patient clinical trial was successfully performed with CRISPR/Cas9-modified human T cell therapy. In this review, a brief overview of currently available techniques is provided, and recent advances in T cell genomic engineering for the enhancement of T cell effector function for therapeutic purposes are discussed.

Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors (ICIs) have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity. Particularly, the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S. Food and Drug Administration (FDA)-approved anti-programmed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies. However, the majority of cancers have low clinical response rates to these ICIs due to poor tumor immunogenicity. Indeed, the cyclic guanosine monophosphate-adenosine monophosphate synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS‒STING‒TBK1) axis is now appreciated as the major signaling pathway in innate immune response across different species. Aberrant signaling of this pathway has been closely linked to multiple diseases, including auto-inflammation, virus infection and cancers. In this perspective, we provide an updated review on the latest progress on the development of small molecule modulators targeting the cGAS‒STING‒TBK1 signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy. Meanwhile, highlights on the clinical candidates, limitations and challenges, as well as future directions in this field are also discussed. Further, small molecule inhibitors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well.

BACKGROUND: We report a case of sustained complete response in unfavorable cancer of unknown primary site (CUP) successfully treated with chemotherapy combining pembrolizumab, pemetrexed and platinum.
METHODS: A 66-year-old man was presented with weight loss and cough for 3 months. Contrast-enhanced computed tomography (CT) confirmed a mass in the superior anterior mediastinum and multiple enlarged mediastinal and axillary lymph nodes. Positron emission tomography-CT (PET-CT) showed abnormal uptake in the corresponding lesions. Histopathological analysis of the left axillary nodule revealed poorly differentiated adenocarcinoma. Immunohistochemistry showed the tumor cells were positive for cytokeratin 7 and thyroid transcription factor-1 and negative for cytokeratin 20. Thus, the patient was diagnosed as poorly differentiated adenocarcinoma of unknown primary, and treated as non-small-cell lung cancer. Additional genetic testing revealed the patient was negative for EGFR, ALK fluorescence in situ hybridization, ROS1, BRAF, and PD-L1 22C3 IHC with Tumor Proportion Score (TPS) was less than 1%. The patient received six cycles of pembrolizumab, platinum, and pemetrexed intravenously. Cisplatin was switched to carboplatin because of cisplatin nephrotoxicity in one course. PET-CT after six cycles showed all lesions disappeared; complete response was considered to have been achieved. Maintenance therapy of pembrolizumab and pemetrexed has been continued for 6 months after the induction therapies to prevent progressive disease. Complete response has been maintained.
CONCLUSIONS: Chemotherapy with pembrolizumab, platinum and pemetrexed could be valuable for treating unfavorable CUP.
CONCLUSIONS: Chemotherapy with pembrolizumab, platinum, and pemetrexed helped achieved sustained complete response in a patient with unfavorable CUP.

Recognizing that guideline-directed histologic grading of endomyocardial biopsy tissue samples for rejection surveillance has limited diagnostic accuracy, quantitative, in situ characterization was performed of several important immune cell types in a retrospective cohort of clinical endomyocardial tissue samples. Differences between cases were identified and were grouped by histologic grade versus clinical rejection trajectory, with significantly increased programmed death ligand 1+, forkhead box P3+, and cluster of differentiation 68+ cells suppressed in clinically evident rejections, especially cases with marked clinical-histologic discordance. Programmed death ligand 1+, forkhead box P3+, and cluster of differentiation 68+ cell proportions are also significantly higher in \"never-rejection\" when compared with \"future-rejection.\" These findings suggest that in situ immune modulators regulate the severity of cardiac allograft rejection.

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