Tumor cells express programmed death ligand 1 (PD-L1) and is a key immune evasion mechanism. PD-L1 expression in multiple breast cancer cell lines was evaluated to identify intrinsic differences that ...affect their potential for immune evasion.
PD-L1 expression was analyzed in six breast cancer cell lines: AU565&MCF7 (luminal), BT20&HCC1143 (basal A), MDA231&HCC38 (basal B). Surface and intracellular PD-L1 expression +/- interferon γ for 48 hours was measured by flow cytometry. PD-L1 gene expression data for all breast cancer cell lines in the Comprehensive Cell Line Encyclopedia (CCLE) was analyzed. Correlation between PD-L1 levels and clinicopathologic parameters was analyzed within Oncomine datasets. A tissue microarray containing 61 invasive breast cancer primary tumor cores was stained for PD-L1 expression and analyzed.
Basal breast cancer cells constitutively express the highest levels of PD-L1. All cell lines increased PD-L1 expression with interferon γ, but basal B cells (MDA-231 and HCC38) demonstrated the largest increases. There were no differences in protein localization between cell lines. In the CCLE data, basal cell lines demonstrated higher mean PD-L1 expression compared to luminal cell lines. High PD-L1 expressing basal cell lines over-express genes involved in invasion, proliferation, and chemoresistance compared to low PD-L1 basal cell lines. High PD-L1 basal cell lines had lower expression of IRF2BP2 and higher STAT1 levels compared to low PD-L1 expressing cell lines. Within Oncomine datasets PDL1 mRNA levels were higher in basal type tumors. The TMA analysis demonstrated that lymph node positive cases had higher levels of PD-L1 protein expression compared to lymph node negative cases.
Basal type breast cancer (especially basal B) express greater levels of PD-L1 constitutively and with IFN γ. High PD-L1 basal cells over-express genes involved in invasion, motility, and chemoresistance. Targeting PD-L1 may enhance eradication of aggressive breast cancer cells by the immune system.
Diagnostic pathology is the foundation and gold standard for identifying carcinomas. However, high inter-observer variability substantially affects productivity in routine pathology and is especially ...ubiquitous in diagnostician-deficient medical centres. Despite rapid growth in computer-aided diagnosis (CAD), the application of whole-slide pathology diagnosis remains impractical. Here, we present a novel pathology whole-slide diagnosis method, powered by artificial intelligence, to address the lack of interpretable diagnosis. The proposed method masters the ability to automate the human-like diagnostic reasoning process and translate gigapixels directly to a series of interpretable predictions, providing second opinions and thereby encouraging consensus in clinics. Moreover, using 913 collected examples of whole-slide data representing patients with bladder cancer, we show that our method matches the performance of 17 pathologists in the diagnosis of urothelial carcinoma. We believe that our method provides an innovative and reliable means for making diagnostic suggestions and can be deployed at low cost as next-generation, artificial intelligence-enhanced CAD technology for use in diagnostic pathology.Diagnostic pathology currently requires substantial human expertise, often with high inter-observer variability. A whole-slide pathology method automates the prediction process and provides computer-aided diagnosis using artificial intelligence.
A 22-Year-Old With a Left Apical Chest Mass Rybolt, Lauren; Oehler, Richard L; Khalil, Farah K ...
Clinical infectious diseases,
01/2024, Letnik:
78, Številka:
1
Journal Article
Recently it has become clear that the cost associated with the Warburg effect, which is inefficient production of ATP, is offset by selective advantages that are produced by resultant intracellular ...metabolic alterations. In fact tumors may be addicted to the Warburg effect. In addition these alterations result in changes in the extracellular tumor microenvironment that can also produce selective advantages for tumor cell growth and survival. One such extracellular alteration is increased adenosine concentrations that have been shown to impair T cell mediated rejection and support angiogenesis. The expression of the A2A receptor in non-small cell cancer (NSCLC) tissues, cell lines and cancer associated fibroblasts (CAF) was determined by performing immunohistrochemistry and immunoblot analysis. The efficacy of the A2A receptor antagonists in vivo was evaluated in a PC9 xenograft model. To determine the mode of cell death induced by A2A receptor antagonists flow cytometry, immunoblot, and cytotoxic analysis were performed. We found that a significant number of lung adenocarcinomas express adenosine A2A receptors. Antagonism of these receptors impaired CAF and tumor cell growth in vitro and inhibited human tumor xenograft growth in mice. These observations add to the rationale for testing adenosine A2A receptor antagonists as anticancer therapeutics. Not only could there be prevention of negative signaling in T cells within the tumor microenvironment and inhibition of angiogenesis, but also an inhibitory effect on tumor-promoting, immunosuppressive CAFs and a direct inhibitory effect on the tumor cells themselves.
A unique 12-chemokine gene expression score (CS) accurately predicted the presence of tumor-localized, ectopic lymph node-like structures (TL-ELNs) and improved overall survival (OS) in primary ...colorectal cancer and metastatic melanoma. We analyzed the correlation between CS, clinicopathological variables, molecular data, and 366 survival in Moffitt Cancer Center's Total Cancer Care (TCC) patients with non-metastatic breast cancer.
Affymetrix gene expression profiles were used to interrogate the CS by the principal component method. Breast tumors were classified as high or low score based on median split, and correlations between clinicopathologic variables, PAM50 molecular subtype, and ELN formation were analyzed using the TCC dataset. Differences in overall survival (OS) and recurrence-free survival (RFS) in the larger KM Plot breast cancer public datasets were compared using Kaplan-Meier curves.
We divided the Total Cancer Care (TCC) breast cancer patients into two groups of high or low CS. Mean CS was 0.24 (range, 2.2-2.1). Patients with higher CS were more likely to be white (172 vs. 159; p = 0.03), had poorly differentiated tumors (112 vs. 59; p <0.0001), ER/PR negative (41 vs. 26) and HER2 positive (36 vs. 19; p = 0.001), and contain TL-ELNs. Higher CS scores were also seen in the basal and HER2+ molecular subtypes. In the KM Plot breast cancer datasets higher CS patients demonstrated superior OS (HR = 0.73, p = 0.008) and RFS (HR 0.76, p = <0.0001), especially in basal and HER2+ patients.
High CS breast tumors tend to be higher grade, basal or HER2+, and present more frequently in Caucasians. However, this group of patients also shows the presence of TL-ELNs within the tumor microenvironment and has better survival outcomes. The CS is a novel tool that can identify breast cancer patients with tumors of a unique intratumoral immune composition and better prognosis. Whether or not the CS is a predictive response marker in breast cancer patients undergoing immunotherapy remains to be determined.
Worldwide, lung cancer is the most common cause of mortality. Toxins from tobacco smoke are known to increase the risk of lung cancer; however, up to 15% of lung cancer-related deaths in men and up ...to 50% of lung cancer-related deaths in women occur in people who do not smoke. Despite the fact that chemotherapy generally provides a survival benefit for non-small-cell lung cancer, not every patient will respond to therapy and many experience therapy-related adverse events. Thus, predictive markers are used to determine which patients are more likely to respond to a given regimen.
We reviewed the current medical literature in English relating to predictive markers that may be positive, such as the presence of an activating EGFR mutation.
The advances in using EGFR as a molecular predictive marker were summarized. This biomarker influences therapeutic response in patients with lung adenocarcinoma. Clinical evidence supporting its value is also reviewed.
The use of EGFR as a predictive factor in lung adenocarcinoma may help target therapy to individual tumors to achieve the best likelihood for long-term survival and to avoid adverse events from medications unlikely to be effective.
Fallopian tube carcinoma (FTC) or tubal carcinoma is an uncommon cancer. Since presenting symptoms of FTC are often nonspecific, most FTC patients present at advanced stages IIIC or IV. For ...early-stage FTC, surgical treatment with or without adjuvant platinum-based chemotherapy is the mainstay, yielding a disease-free survival rate at 5 years approaching 100%. ...Ragusa et al described two cases of patients with ovarian cancer with isolated cardiophrenic angle node metastasis. 4 It was hypothesized that cardiophrenic angle node, especially the right side, was susceptible to metastatic deposit due to the anatomic arrangement of peritoneal fluid drainage, which follows a clockwise route, exposing first the thoracic lymphatic stations on the right side. 4 Our experience lends support to this hypothesis.
Lung cancer is the leading cause of cancer deaths in the United States. Novel lung cancer targeted therapeutic and molecular imaging agents are needed to improve outcomes and enable personalized ...care. Since these agents typically cannot cross the plasma membrane while carrying cytotoxic payload or imaging contrast, discovery of cell-surface targets is a necessary initial step. Herein, we report the discovery and characterization of lung cancer cell-surface markers for use in development of targeted agents. To identify putative cell-surface markers, existing microarray gene expression data from patient specimens were analyzed to select markers with differential expression in lung cancer compared to normal lung. Greater than 200 putative cell-surface markers were identified as being overexpressed in lung cancers. Ten cell-surface markers (CA9, CA12, CXorf61, DSG3, FAT2, GPR87, KISS1R, LYPD3, SLC7A11 and TMPRSS4) were selected based on differential mRNA expression in lung tumors vs. non-neoplastic lung samples and other normal tissues, and other considerations involving known biology and targeting moieties. Protein expression was confirmed by immunohistochemistry (IHC) staining and scoring of patient tumor and normal tissue samples. As further validation, marker expression was determined in lung cancer cell lines using microarray data and Kaplan-Meier survival analyses were performed for each of the markers using patient clinical data. High expression for six of the markers (CA9, CA12, CXorf61, GPR87, LYPD3, and SLC7A11) was significantly associated with worse survival. These markers should be useful for the development of novel targeted imaging probes or therapeutics for use in personalized care of lung cancer patients.
Background
Juvenile‐onset recurrent respiratory papillomatosis (JO‐RRP) is a human papilloma virus‐mediated progressive benign neoplasm that affects children and young adults. Primary management ...consists of regular surgical debulking to maintain airway patency and vocal function. Like condyloma acuminata, JO‐RRP is associated with immune dysregulation, and T cells isolated from papillomas express an anergic phenotype. Therefore, we hypothesized that programmed death protein 1 axis inhibition could stabilize tumor growth.
Materials and Methods
We treated two patients with refractory JO‐RRP using nivolumab, with the primary objective of assessing clinical activity. We explored baseline papilloma features using immunohistochemistry and comprehensive genomic profiling.
Results
Both patients experienced symptomatic improvement, and interval laryngoscopies revealed a reduction in papillomatosis burden. One patient has not required subsequent surgical debridement for almost 2 years. On pathologic examination of pretreatment papillomas from both cases, infiltrating T cells were evident in the papilloma stroma, and papilloma programmed death ligand 1 expression was absent. Papilloma mutational load ranged between three and six mutations per megabase for each case. From on‐treatment biopsy tissue, a higher amount of intraepithelial T cells and programmed death ligand 1 expression were detected in the papilloma.
Conclusion
Nivolumab appears to have promising activity in JO‐RRP, and further clinical investigation with more patients in clinical trials is warranted.
Implications for Practice
To the authors' knowledge, this article is the first report describing clinical activity with a programed cell death‐1 (PD‐1) inhibitor to treat a rare but detrimental type of respiratory tract epithelial neoplasm that afflicts young adults. Two patients were treated, and tumor features, such as mutational load, were examined with the intent to stimulate future hypotheses for translational research. The safety and activity of PD‐1 inhibitors in this population still need to be corroborated in clinical trials and should not yet be adopted into clinical practice.
Juvenile onset recurrent respiratory papillomatosis (JO‐RRP) is a benign neoplasm of the larynx that affects children and young adults. This article assesses the clinical activity of nivolumab treatment in two patients with JO‐RRP.
RET-rearrangement occurs in 1 to 2% of patients with non-small cell lung cancer (NSCLC), typically among non-smokers, and it is associated with an increased incidence of brain metastasis. While ...selpercatinib and pralsetinib are active for RET-rearranged NSCLC, the optimal standard frontline regimen for this clinical setting remains undefined. Here, we report on a patient with RET-rearranged NSCLC who received frontline pembrolizumab and achieved a complete tumor response lasting for 29 months and ongoing. Single-agent ICI can be an effective frontline treatment for RET-rearranged NSCLC.
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