scholarly journals Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 284
Author(s):  
Peng Zhang ◽  
Xinxin Xiong ◽  
Christian Rolfo ◽  
Xuexiang Du ◽  
Yan Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Clinical Development ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Cancer Types ◽  
New Generation

Background: CTLA-4 was the first immune checkpoint targeted for cancer therapy and the first target validated by the FDA (Food and Drug Administration) after approval of the anti-CTLA-4 antibody, Ipilimumab. However, clinical response rates to anti-CTLA-4 antibodies are lower while the rates of immunotherapy-related adverse events (irAE) are higher than with anti-PD-1 antibodies. As a result, the effort to target CTLA-4 for cancer immunotherapy has stagnated. To reinvigorate CTLA-4-targeted immunotherapy, we and others have reported that rather than blocking CTLA-4 interaction with its cognate targets, CD80 and CD86, anti-CTLA-4 antibodies achieve their therapeutic responses through selective depletion of regulatory T cells in the tumor microenvironment. Accordingly, we have developed a new generation of anti-CTLA-4 antibodies with reduced irAE and enhanced antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/ADCP). A major unresolved issue is how to select appropriate cancer types for future clinical development. Methods: We generated a landscape of the immune tumor microenvironment from RNAseq and genomic data of 7279 independent cancer samples belonging to 22 cancer types from The Cancer Genomics Atlas (TCGA) database. Based primarily on genomic and RNAseq data from pre-treatment clinical samples of melanoma patients who were later identified as responders and nonresponders to the anti-CTLA-4 antibody Ipilimumab, we identified 5 ranking components of responsiveness to anti-CTLA-4, including CTLA-4 gene expression, ADCC potential, mutation burden, as well as gene enrichment and cellular composition that favor CTLA-4 responsiveness. The total ranking number was calculated by the sum of 5 independent partitioning values, each comprised of 1–3 components. Results: Our analyses predict metastatic melanoma as the most responsive cancer, as expected. Surprisingly, non-small cell lung carcinoma (NSCLC) is predicted to be highly responsive to anti-CTLA-4 antibodies. Single-cell RNAseq analysis and flow cytometry of human NSCLC-infiltrating T cells supports the potential of anti-CTLA-4 antibodies to selectively deplete intratumoral Treg. Conclusions: Our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies. Our approach provides an objective ranking of the sensitivity of human cancers to anti-CTLA-4 antibodies. The comprehensive ranking of major cancer types provides a roadmap for clinical development of the next generation of anti-CTLA-4 antibodies.

scholarly journals An Efficient Strategy to Induce and Maintain In Vitro Human T Cells Specific for Autologous Non-Small Cell Lung Carcinoma

PLoS ONE ◽  
2010 ◽  
Vol 5 (8) ◽  
pp. e12014 ◽  
Author(s):  
Glenda Canderan ◽  
Paola Gruarin ◽  
Daniela Montagna ◽  
Raffaella Fontana ◽  
Giulio Melloni ◽  
...  
Keyword(s):  
T Cells ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Efficient Strategy ◽  
Human T Cells

scholarly journals The positive prognostic effect of stromal CD8+ tumor-infiltrating T cells is restrained by the expression of HLA-E in non-small cell lung carcinoma

Oncotarget ◽  
2015 ◽  
Vol 7 (3) ◽  
pp. 3477-3488 ◽  
Author(s):  
Mehrdad Talebian Yazdi ◽  
Sander van Riet ◽  
Annemarie van Schadewijk ◽  
Marta Fiocco ◽  
Thorbald van Hall ◽  
...  
Keyword(s):  
T Cells ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Prognostic Effect

The association between CD4+ CD25+ regulatory T cells and non-small cell lung carcinoma

2013 ◽  
Vol 23 (5) ◽  
pp. 1575-1581
Author(s):  
Mohamed Abul-Dahab ◽  
Shereen Mohamed Elhoseiny ◽  
Irene Mohamed Sabry
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma

scholarly journals Early detection of the major male cancer types in blood-based liquid biopsies using a DNA methylation panel

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Vera Constâncio ◽  
Sandra P. Nunes ◽  
Catarina Moreira-Barbosa ◽  
Rui Freitas ◽  
Jorge Oliveira ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Early Detection ◽  
Minimally Invasive ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Liquid Biopsies ◽  
Cell Lung Carcinoma ◽  
Cancer Types

Abstract Background Lung (LC), prostate (PCa) and colorectal (CRC) cancers are the most incident in males worldwide. Despite recent advances, optimal population-based cancer screening methods remain an unmet need. Due to its early onset, cancer specificity and accessibility in body fluids, aberrant DNA promoter methylation might be a valuable minimally invasive tool for early cancer detection. Herein, we aimed to develop a minimally invasive methylation-based test for simultaneous early detection of LC, PCa and CRC in males, using liquid biopsies. Results Circulating cell-free DNA was extracted from 102 LC, 121 PCa and 100 CRC patients and 136 asymptomatic donors’ plasma samples. Sodium-bisulfite modification and whole-genome amplification was performed. Promoter methylation levels of APCme, FOXA1me, GSTP1me, HOXD3me, RARβ2me, RASSF1Ame, SEPT9me and SOX17me were assessed by multiplex quantitative methylation-specific PCR. SEPT9me and SOX17me were the only biomarkers shared by all three cancer types, although they detected CRC with limited sensitivity. A “PanCancer” panel (FOXA1me, RARβ2me and RASSF1Ame) detected LC and PCa with 64% sensitivity and 70% specificity, complemented with “CancerType” panel (GSTP1me and SOX17me) which discriminated between LC and PCa with 93% specificity, but with modest sensitivity. Moreover, a HOXD3me and RASSF1Ame panel discriminated small cell lung carcinoma from non-small cell lung carcinoma with 75% sensitivity, 88% specificity, 6.5 LR+ and 0.28 LR–. An APCme and RASSF1Ame panel independently predicted disease-specific mortality in LC patients. Conclusions We concluded that a DNA methylation-based test in liquid biopsies might enable minimally invasive screening of LC and PCa, improving patient compliance and reducing healthcare costs. Moreover, it might assist in LC subtyping and prognostication.

scholarly journals New Insights on Old Biomarkers Involved in Tumor Microenvironment Changes and Their Diagnostic Relevance in Non-Small Cell Lung Carcinoma

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1208
Author(s):  
Katarzyna Wadowska ◽  
Piotr Błasiak ◽  
Adam Rzechonek ◽  
Iwona Bil-Lula ◽  
Mariola Śliwińska-Mossoń
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Auc Value

Background: Lung cancer is a multifactorial disease with a heterogeneous tumor group that hampers diagnostic and therapeutic approaches, as well as understanding of the processes that underlie its pathogenesis. Current research efforts are focused on examining alterations in the tumor microenvironment, which may affect the pathogenesis and further malignant progression in lung cancer. The aim of this study was to investigate changes in the levels of biomarkers involved in the lung tumor microenvironment and their diagnostic utility in differentiating lung cancer subtypes and stages. Methods: This study comprised 112 lung cancer patients, 50 with adenocarcinoma, 35 with squamous cell carcinoma, 13 with other non-small cell lung carcinoma subtypes, and 14 with other lung neoplasms than non-small cell lung carcinoma. Tumor markers (CEA, CYFRA 21-1, and NSE) were measured in the patients’ sera and plasmas, along with IL-6, TNF-α, SAA1, CRP, MMP-2, MMP-9, glucose, lactate, and LDH, utilizing enzyme-linked immunosorbent assays, enzyme immunoassays, and automated clinical chemistry and turbidimetry systems. The results were statistically analyzed across patient groups based on the subtype and stage of lung cancer. Results: Glucose concentrations showed statistically significant (p < 0.05) differences both between lung cancer subtypes and stages, with the highest levels in patients with other lung neoplasms (me = 130.5 mg/dL) and in patients with stage IIB lung cancer (me = 132.0 mg/dL). In patients with advanced lung cancer, IL-6 and LDH had considerably higher concentration and activity. There was also a significant positive correlation between IL-6 and MMP-9 in adenocarcinoma and SqCC, with correlation coefficients of 0.53 and 0.49, respectively. The ROC analyses showed that the best single biomarkers for distinguishing adenocarcinoma from squamous cell carcinoma are glucose, CRP, and CYFRA 21-1; however, their combination did not significantly improve sensitivity, specificity, and the AUC value. The combinations of IL-6, glucose, LDH and CEA, IL-6, SAA1, MMP-9, and lactate can distinguish patients with stage IIB lung cancer from those with stage IIA with 100% sensitivity, 100% specificity, and with an AUC value of 0.8333 and 1.0000, respectively, whereas the combination of CEA, IL-6, and LDH can identify patients with stage IIIA lung cancer from those with stage IIB with 72.73% sensitivity, 94.44% specificity, and an AUC value of 0.8686. Conclusion: There is a link between biomarkers of tumor microenvironment changes and tumor markers, and combinations of these markers may be clinically useful in the differential diagnosis of adenocarcinoma and squamous cell carcinoma, as well as lung cancer stages IIB and IIA, and IIIA and IIB.

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