UNASSIGNED: The efficacy of immunotherapy for brain metastases from small cell lung cancer (SCLC) is relatively low, and the tumor microenvironment of SCLC brain metastases is still unknown. Therefore, we investigated the distribution of tumor-infiltrating lymphocytes (TILs) and the expression of programmed cell death-ligand 1 (PD-L1) in patients with brain metastases from SCLC to explore the tumor microenvironment of SCLC brain metastases.
UNASSIGNED: A retrospective analysis was performed on 12 surgical specimens of brain metastases from patients with SCLC treated in the Department of Neurosurgery of The First Affiliated Hospital of Anhui Medical University from June 2017 to June 2022. The inclusion criteria for this study were the following: (I) a pathologically confirmed diagnosis of SCLC brain metastases; (II) surgical resection of brain metastases; (III) age >18 years; (IV) and complete clinical data. Patient-related data were retrieved from the inpatient medical record system, telephone follow-up of patients date of death, and overall survival (OS). The immunofluorescence-based tissue microenvironment analysis panel (MAP) was utilized for the detection of TILs, including CD3, CD8, programmed cell death 1 (PD-1), and PD-L1, in formalin-fixed and paraffin-embedded archival specimens of brain metastases. The expression levels of PD-L1 in tumor cells were detected by immunohistochemistry. The correlation between the OS and the above-mentioned markers was analyzed in the 12 patients.
UNASSIGNED: Twelve patients were included in the study. The patients\' ages ranged from 51-78 years with a median of 68 years, with 1 female and 11 males. Among 12 patients with SCLC brain metastases: positive rates of CD3+ TILs in the tumor parenchyma vs. tumor stroma were 0.60%±0.94% vs. 1.76%±2.72% (P=0.01), respectively; positive rates of CD8+ TILs in the tumor parenchyma vs. tumor stroma were 0.80%±0.78% vs. 2.46%±3.72% (P=0.02), respectively. There was no co-expression of CD8+ and PD-1+ TILs in the tumor parenchyma of 11 cases, and the infiltration density of coexpressed CD3+ and PD-1+ TILs was more than 10/mm2 in only 1 case. There was no coexpression of CD3+ and PD-1+ TIL in the stroma of 10 cases, and the infiltration density of CD8+ and PD-1+ TILs was more than 10/mm2 in 2 cases. Immunohistochemistry was used to detect the expression of PD-L1 in 12 cases of SCLC metastatic lesions, and 3 cases (25%) were positive. Survival analysis showed that patients with positive intraepithelial CD3+ TILs had significantly longer OS [hazard ratio 3.383, 95% confidence interval (CI): 0.959-11.940; P=0.04].
UNASSIGNED: Our study further demonstrated the immune microenvironment of SCLC brain metastases. The distribution of TILs in SCLC brain metastases is low and mainly distributed in the stroma, with the expression of PD-L1 in these tumor tissues being low. Further exploration of the immune microenvironment of SCLC brain metastases is of great significance for potential treatment.

UNASSIGNED: The tumor microenvironment (TME) plays an important role in tumor progression and immunotherapy responses in non-small cell lung cancer (NSCLC). The programmed cell death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) checkpoint is a central mediator of immunosuppression in the TME. However, there is still a need to identify additional biomarkers that could reflect the difference in TME and PD-L1 expression in NSCLC patients. To this end, we focused on the expression of G-protein-coupled receptor family C group 5 type A (GPRC5A) in NSCLC. GPRC5A, is a retinoic acid-inducible gene that plays multiple roles in NSCLC. However, little is known about the role of GPRC5A in regulating the TME and PD-L1. Our objective was to describe the critical role of GPRC5A expression in NSCLC in the setting of immune cell infiltration.
UNASSIGNED: We identified the relationship between GPRC5A expression and the clinicopathologic characteristics of NSCLC patients in the Fudan University Shanghai Cancer Center (FUSCC) cohort. Furthermore, we validated GPRC5A as a predictive biomarker by using public databases to reveal the relationship between GPRC5A expression and immune cell infiltration. To correlate the expression of GPRC5A with the spatial distribution of PD-L1 in NSCLC samples, we performed multiplex immunohistochemistry (mIHC).
UNASSIGNED: Low GPRC5A expression is associated with earlier pathological stage (pStage). Analysis of immune cell infiltration indicates there is a relationship between low GPRC5A expression and increased infiltration of CD8+ T cells, activated CD4+ T cells, and M1 macrophages within the TME. Furthermore, low GPRC5A expression is associated with an increased immunophenotype score (IPS) in NSCLC. Additionally, analysis of mIHC reveals there is a correlation between low GPRC5A expression and spatial distribution of tumoral PD-L1 expression.
UNASSIGNED: Our study revealed the relationship between low expression of GPRC5A and earlier pStage in NSCLC. Furthermore, we observed that low expression of GPRC5A is associated with increased infiltration of immune cells, higher IPS, and spatial distribution of PD-L1-positive tumor cells. Therefore, we speculate that low expression of GPRC5A is associated with immunotherapy, but further validation is still required.

UNASSIGNED: Triple negative breast cancer (TNBC) represents a highly aggressive breast cancer subtype, historically managed with chemotherapy regimens predominantly involving anthracyclines and taxanes, yielding unfavorable prognoses. This review endeavors to offer a thorough examination of the present state of treatment strategies for early stage triple negative breast cancer (eTNBC), with a particular emphasis on immunotherapy modalities, combination therapies, predictive biomarkers, and ongoing clinical trials. The principal aim of this review is to meticulously assess the available literature, ascertain significant discoveries, and engage in discussions regarding their potential implications for future research endeavors, clinical applications, and policy formulation.
UNASSIGNED: This review was conducted using PubMed and Google Scholar databases, with the latest update performed in March 2023. The search strategy was designed to ensure a comprehensive analysis of the literature, with a focus on recent advancements.
UNASSIGNED: We critically assess the current eTNBC treatment landscape, covering efficacy and limitations of monotherapy, combination therapies, and predictive biomarkers. We highlight promising results from recent trials, address controversies surrounding chemotherapy, and explore optimal approaches for adjuvant and neoadjuvant therapy (NAT). Insights into personalized treatment strategies, ongoing trials, and future perspectives are provided, advancing our understanding of therapeutic options for eTNBC.
UNASSIGNED: Through a comprehensive analysis of the literature, this review highlights the potential of immunotherapy, particularly in combination with chemotherapy, as a promising approach for treating eTNBC. However, further research is warranted to optimize treatment strategies, refine patient selection criteria, and identify reliable biomarkers for predicting response to immune checkpoint inhibitors (ICIs). The findings of this review hold significant implications for future research, clinical practice, and policy-making, offering valuable insights into the current challenges and advancements in eTNBC treatment. Ultimately, this knowledge can contribute to improved patient outcomes, enhanced quality of life, and the development of more effective therapeutic approaches for eTNBC.

BACKGROUND: Primary cardiac angiosarcoma(PCA) has a low incidence rate and poor prognosis. Currently, no unified clinical treatment standards are available.
METHODS: We report the case of a 48-year-old man presenting chest tightness, breathlessness, and dyspnea. Imaging and postoperative histopathologic studies confirmed PCA and that the tumor had invaded the entire right atrium. The patient developed progressive disease (PD) during postoperative radiotherapy. We used immunotherapy combined with targeted therapy based on the results of molecular profile and evaluation of tertiary lymphoid structures (TLSs) and programmed cell death-ligand 1 (PD-L1). After treatment, the metastatic lymph nodes of the patient were reduced to a certain extent, indicating that combination therapy was effective.
CONCLUSIONS: To the best of our knowledge, this is the first report of radiotherapy combined with anti-PD-1 and tyrosine kinase inhibitors(TKI) for PCA. In addition, this is the first report on immunotherapy for PCA based on new evaluation methods, including TLSs, PD-L1, and genomic profile.

Evidence recently showed that pleiotropic cytokine interferon-gamma (IFN-γ) in the tumor microenvironment (TME) plays a positive role in hepatocellular carcinoma (HCC) progression through the regulation of liver cancer stem cells (LCSCs) in HCC. The present study explored the role and potential mechanism of mitochondrial programmed cell death-ligand 1 (PD-L1) and its regulation of ferroptosis in modulating the cancer stemness of LCSCs. It was shown that mimicking TME IFN-γ exposure increased the LCSCs ratio and cancer stemness phenotypes in HCC cells. IFN-γ exposure inhibited sorafenib (Sora)-induced ferroptosis by enhancing glutathione peroxidase 4 (GPX4) expression as well reactive oxygen species (ROS) and lipid peroxidation (LPO) generation in LCSCs. Furthermore, IFN-γ exposure upregulated PD-L1 expression and its mitochondrial translocation, inducing dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and correlating with glycolytic metabolism reprogramming in LCSCs. The genetic intervention of PD-L1 promoted ferroptosis-dependent anti-tumor effects of Sora, reduced glycolytic metabolism reprogramming, and inhibited cancer stemness of HCC in vitro and in vivo. Our results revealed a novel mechanism that IFN-γ exposure-induced mitochondrial translocation of PD-L1 enhanced glycolytic reprogramming to mediate the GPX4-dependent ferroptosis resistance and cancer stemness in LCSCs. This study provided new insights into the role of mitochondrial PD-L1-Drp1-GPX4 signal axis in regulating IFN-γ exposure-associated cancer stemness in LCSCs and verified that PD-L1-targeted intervention in combination with Sora might achieve promising synergistic anti-HCC effects.

More than 60 years ago, disulfiram (DSF) was employed for the management of alcohol addiction. This promising cancer therapeutic agent inhibits proliferation, migration, and invasion of malignant tumor cells. Furthermore, divalent copper ions can enhance the antitumor effects of DSF. Molecular structure, pharmacokinetics, signaling pathways, mechanisms of action and current clinical results of DSF are summarized here. Additionally, our attention is directed towards the immunomodulatory properties of DSF and we explore novel administration methods that may address the limitations associated with antitumor treatments based on DSF. Despite the promising potential of these various delivery methods for utilizing DSF as an effective anticancer agent, further investigation is essential in order to extensively evaluate the safety and efficacy of these delivery systems.

UNASSIGNED: Lung adenocarcinoma, as a common histological type in lung cancer, the overall survival is very low, and the prognosis is poor because it is difficult to find and easily recurs. Therefore, this study aimed to explore the role of the secreted protein beta-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) in the development of lung adenocarcinoma and to evaluate its potential significance for early clinical biomarker screening.
UNASSIGNED: The mRNA expression profiles of patients with lung adenocarcinoma and normal controls were analyzed via The Cancer Genome Atlas (TCGA) database. Serum samples of clinical lung cancer patients and healthy people were obtained, and the differences in B3GNT3 expression in different stages of lung adenocarcinoma and in healthy tissues were compared. Kaplan-Meier (K-M) curves were drawn to clarify the influence of high and low expression of B3GNT3 on the prognosis of patients. Peripheral blood samples from patients with lung adenocarcinoma and healthy people were obtained clinically, and receiver operating characteristic (ROC) curves were drawn to clarify the sensitivity and specificity of B3GNT3 expression for the diagnosis of lung adenocarcinoma. Lung adenocarcinoma cells were cultured in vitro, the expression of B3GNT3 was knocked down by lentivirus infection. The expression of the apoptosis-associated genes was detected by reverse transcription-polymerase chain reaction (RT-PCR).
UNASSIGNED: The secreted protein B3GNT3 is significantly differentially expressed in the serum of patients with lung adenocarcinoma versus normal controls. Subgroup analysis according to lung adenocarcinoma clinical stage showed that the higher the clinical stage of lung adenocarcinoma was, the higher the B3GNT3 expression. Enzyme-linked immunosorbent assay (ELISA) revealed that B3GNT3 expression was significantly increased in the serum of patients with lung adenocarcinoma and significantly decreased after surgery. By inhibiting programmed cell death-ligand 1 (PD-L1), the level of apoptosis was significantly increased and the proliferative capacity was significantly inhibited. In contrast, the level of apoptosis was significantly increased and the proliferation ability was significantly inhibited after simultaneous overexpression of B3GNT3 and inhibition of PD-L1.
UNASSIGNED: High expression of the secreted protein B3GNT3 in lung adenocarcinoma is closely related to prognosis and can serve as a potential biological marker for the early screening of lung adenocarcinoma.

UNASSIGNED: Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the world. Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) indicated for NSCLC that effectively targets sensitive epidermal growth factor receptor mutation and exon20 T790M. Despite initially impressive outcomes, acquired resistance (AR) develops rapidly, typically within 9-13 months, and the mechanisms of resistance are not fully understood. Over the past years, EGFR-TKI and programmed cell death-ligand 1 (PD-L1) inhibitors have been widely used to treat for patients with advanced lung adenocarcinoma.
UNASSIGNED: Herein we report a middle-aged female who suffered from lung adenocarcinoma based on the pathological diagnosis. Epidermal growth factor receptor exon 19 deletion was detected by next-generation sequencing (NGS). After the patient underwent a series of treatments, including osimertinib, BTN2A1-BRAF fusion was identified. After assessing PD-L1 expression by immunohistochemistry (IHC), the patient was switched to duvalizumab, a PD-L1 inhibitor, but no significant improvements were observed. NGS and IHC assays were conducted to analyze the biopsy and blood samples obtained during treatment.
UNASSIGNED: This case substantiates that the acquisition of BTN2A1-BRAF fusion potentially serves as a mechanism of AR to osimertinib in NSCLC. Patients with sensitive epidermal growth factor receptor mutation derive minimal benefit from PD-L1 inhibitors irrespective of the degree of PD-L1 expression in the tumor tissue in IHC. Our case provides a new train of thought for treating this patient population.

Immunological evasion is one of the defining characteristics of cancers, as the immune modification of an immune checkpoint (IC) confers immune evasion capabilities to tumor cells. Multiple ICs, such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), can bind to their respective receptors and reduce tumor immunity in a variety of ways, including blocking immune cell activation signals. IC blockade (ICB) therapies targeting these checkpoint molecules have demonstrated significant clinical benefits. This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers. Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment. In this review, we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels, including epigenetic regulation, transcriptional regulation, and post-translational modifications. In addition, we provide a summary of the medications targeting various nodes in the regulatory pathway, and highlight the potential of newly identified IC molecules, focusing on their potential implications for cancer diagnostics and immunotherapy.

UNASSIGNED: This study sought to depict the genomic landscape of patients with surgically resected lung squamous cell carcinoma (LUSC) and its relationship with clinical outcome indicators.
UNASSIGNED: We retrospectively collected the clinical data of 180 patients from the electronic medical records and applied targeted sequencing and immunohistochemistry (IHC) to depict the genomic landscape, including the tumor mutation burden (TMB), programmed cell death-ligand 1 (PD-L1), and cluster of differentiation CD8+ tumor-infiltrating lymphocytes (CD8+ TILs). And comparative analysis and survival analysis of these parameters were conducted to find prognostic factors for clinical outcome.
UNASSIGNED: PD-L1+ tumor cells were observed in 75 (41.7%) of the patients, the median rate of CD8+ TILs was 11.5 [4, 24], and the median TMB was 9.4 (7.5-13.7) mutations per megabase (mut/Mb). Patched receptor 1 (PTCH1) gene mutation frequency was significantly associated with CD8+ TILs density (12% vs. 1%; P=0.024). High PD-L1 expression and CD8+ TILs+ were significantly associated with longer disease-free survival (DFS), and a further subgroup analysis revealed that both were significantly correlated with the DFS of stage I/II patients but not stage III patients.
UNASSIGNED: The results suggest that only PTCH1 gene mutation frequency was correlated with CD8+ TILs density. Additionally, intense CD8+ TILs density and high PD-L1 expression were found to be associated with longer DFS. Our findings provide insights into the precise treatment strategy for surgically resected LUSC patients.