scholarly journals Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

2020 ◽  
Author(s):  
Ming Chen ◽  
Runzhe Chen ◽  
Ying Jin ◽  
Jun Li ◽  
Jiexin Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cell Receptor ◽  
Small Cell ◽  
Intratumor Heterogeneity ◽  
High Recurrence Rate ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Tcr Repertoire

AbstractSmall-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, we revealed a rather homogeneous mutational landscape but extremely suppressed and heterogeneous T cell receptor (TCR) repertoire in SCLCs. Higher mutational burden, lower chromosomal copy number aberration (CNA) burden, less CNA ITH and less TCR ITH were associated with longer overall survival of SCLC patients. Compared to non-small cell lung cancers (NSCLCs), SCLCs had similar predicted neoantigen burden and mutational ITH, but significantly more suppressed and heterogeneous TCR repertoire that may be associated with higher CNA burden and CNA ITH in SCLC. Novel therapeutic strategies targeting CNA could potentially improve the tumor immune microenvironment and response to immunotherapy in SCLC.

scholarly journals Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

2021 ◽  
Author(s):  
Ming Chen ◽  
Runzhe Chen ◽  
Ying Jin ◽  
Jun Li ◽  
Jiexin Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cell Receptor ◽  
Small Cell ◽  
Intratumor Heterogeneity ◽  
High Recurrence Rate ◽  
Small Cell Lung ◽  
Tcr Repertoire

Abstract Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry (IHC), we revealed a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC (LS-SCLC) tumors. Compared to localized non-small cell lung cancers (NSCLCs), LS-SCLCs had similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression were associated with longer overall survival (OS), while higher CNA burden were associated with shorter OS in patients with LS-SCLC.

A novel noninvasive biomarker based on peripheral PD-1posi CD8 T-cell receptor repertoire correlated with clinical outcomes to immunotherapy in non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14174-e14174
Author(s):  
Jie-Fei Han ◽  
Zhijie Wang ◽  
Hua Bai ◽  
Si Chen ◽  
Yuqi Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Cell Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Non Invasive ◽  
Tcr Repertoire ◽  
Tcr Diversity

e14174 Background: Although advances on exploration of biomarkers personalized the immune checkpoint blockades (ICBs) delivery, non-invasive blood-based approach remainsan intriguing area for further investigation.This study investigated the feasibility of peripheral isolated PD-1posiCD8T cell receptor (TCR) repertoire profiling in predicting the clinical outcomes of ICBs treatment for non-small cell lung cancer (NSCLC) patients. Methods: The study comprised two independent cohorts (A and B), ultimately recruiting total 40 from 51 patients with stage IIIB-IV NSCLCs who received anti-PD-1/PD-L1 therapy between March 14, 2017 and May 2, 2018. Peripheral blood samples of pre- and post-ICBs (the timepoint of first imaging evaluation) were prospectively collected, and PD-1posiCD8 T cells were isolated by flow cytometry for TCR sequencing. The diversity and clonality of the TCR repertoire were calculated for biomarker profiling. Cohort A (n = 25) was used as a training set for discovery of TCR diversity in the prediction of response to ICBs, and cohort B (n = 15) as a validation set. Progression-free survival (PFS) and response to ICBs treatment were correlated with TCR diversity and clonality. Results: In cohort A, patients with high pre-ICBs PD-1posiCD8 TCR diversity had longer PFS than those with low diversity (6.5 vs. 2.6 months, p = .045), which were substantially validated in cohort B. By using the incorporated set, pre-ICBs PD-1posiCD8 TCR diversity exhibited an optimal Youden's index of 0.81 with a sensitivity of 0.87 and a specificity of 0.94 in clarifying clinical response of ICBs (PR+SD vs. PD). Patients with increased PD-1posiCD8 TCR clonality demonstrated significantly improved PFS (7.3 vs. 2.7 months, p = .005) compared to those with decreased TCR clonality. Interestingly, two patients with initial pseudo-PD exhibited similar change of TCR clonality and expansion of dominant TCR clones with those with PR, but not PD. Conclusions: Peripheral PD-1posiCD8 TCR repertoire sequencing might be a promising non-invasive approach for selecting patients who could benefit from ICBs treatment, which guaranteed the further investigation and validation by larger cohorts.

scholarly journals Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ming Chen ◽  
Runzhe Chen ◽  
Ying Jin ◽  
Jun Li ◽  
Xin Hu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Copy Number ◽  
Small Cell ◽  
High Recurrence Rate ◽  
Copy Number Loss ◽  
Small Cell Lung ◽  
Tcr Repertoire

AbstractSmall-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC.

Exhaustive Review on Lung Cancers: Novel Technologies

2019 ◽  
Vol 15 (9) ◽  
pp. 873-883
Author(s):  
Sajad Khan ◽  
Shahid Ali ◽  
Muhammad
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Therapy ◽  
Small Cell ◽  
X Rays ◽  
Small Cell Lung ◽  
Microscopic Appearance ◽  
Lung Cancers ◽  
Novel Technologies

Background:Lung cancers or (Bronchogenic-Carcinomas) are the disease in certain parts of the lungs in which irresistible multiplication of abnormal cells leads to the inception of a tumor. Lung cancers consisting of two substantial forms based on the microscopic appearance of tumor cells are: Non-Small-Cell-Lung-Cancer (NSCLC) (80 to 85%) and Small-Cell-Lung-Cancer (SCLC) (15 to 20%).Discussion:Lung cancers are existing luxuriantly across the globe and the most prominent cause of death in advanced countries (USA & UK). There are many causes of lung cancers in which the utmost imperative aspect is the cigarette smoking. During the early stage, there is no perspicuous sign/symptoms but later many symptoms emerge in the infected individual such as insomnia, headache, pain, loss of appetite, fatigue, coughing etc. Lung cancers can be diagnosed in many ways, such as history, physical examination, chest X-rays and biopsy. However, after the diagnosis and confirmation of lung carcinoma, various treatment approaches are existing for curing of cancer in different stages such as surgery, radiation therapy, chemotherapy, and immune therapy. Currently, novel techniques merged that revealed advancements in detection and curing of lung cancer in which mainly includes: microarray analysis, gene expression profiling.Conclusion:Consequently, the purpose of the current analysis is to specify and epitomize the novel literature pertaining to the development of cancerous cells in different parts of the lung, various preeminent approaches of prevention, efficient diagnostic procedure, and treatments along with novel technologies for inhibition of cancerous cell growth in advance stages.

scholarly journals Possible involvement of the Hedgehog and PDPK1–Akt pathways in the growth and migration of small-cell lung cancer

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110165
Author(s):  
Naiwang Tang ◽  
Bin Hu ◽  
Yin Zhang ◽  
Zhiwei Chen ◽  
Ronghuan Yu
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Molecular Mechanisms ◽  
Patient Characteristics ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
And Migration ◽  
Proliferation And Migration

Background Small-cell lung cancer (SCLC) accounts for approximately 15% to 20% of all lung cancers, and it is the leading cause of tumor-related deaths globally. This study explored the molecular mechanisms underlying the development of SCLC. Methods The correlations of phosphoinositide-dependent kinase-1 (PDPK1), p-Akt, and Hedgehog expression with patient characteristics were analyzed using SCLC specimens, and their expression was measured in BEAS-2B cells (control) and the SCLC cell lines H82, H69, H446, H146, and H526. Transfection experiments were performed to inhibit or activate gene expression in cells. We then measured the proliferation and migration of H146 cells. Results PDPK1, p-Akt, and Hedgehog expression was significantly higher in SCLC tissues, and their expression was correlated with patient characteristics. p-Akt expression was significantly correlated with Hedgehog expression. In H146 cells, PDPK1 and p-Akt were significantly upregulated. Silencing of PDPK1 or Akt and inhibition of Hedgehog significantly inhibited the proliferation and migration of H146 cells. PDPK1 and Akt affected Hedgehog expression, but Hedgehog did not affect PDPK1 or p-Akt expression. Conclusions The interaction between the PDPK1–Akt pathway and the Hedgehog pathway influences the prognosis, growth, and migration of SCLC.

scholarly journals Identification of a potent kinase inhibitor targeting EML4-ALK fusion protein in non-small cell lung cancer

MedChemComm ◽  
2017 ◽  
Vol 8 (10) ◽  
pp. 1914-1918
Author(s):  
Lian-Xiang Luo ◽  
Ying Li ◽  
Yu-Zhen Niu ◽  
Yu-Wei Wang ◽  
Qian-Qian Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Fusion Protein ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Alk Inhibitor

Herein, we reported 5067-0952, a potent ALK inhibitor with pharmacological efficacy in non-small cell lung cancers harboring the ALK fusion oncogene.

scholarly journals Small cell lung cancer transformation during antitumor therapies: A systematic review

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 1160-1167
Author(s):  
Xing Chai ◽  
Xinru Zhang ◽  
Wenqian Li ◽  
Jin Chai
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Treatment Strategies ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Histological Transformation ◽  
Nsclc Patients

Abstract Lung cancer is the most common cause of cancer-related death. Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the two major histological categories of lung cancers. Drug resistance is a great challenge for cancer treatment, and histological transformation from NSCLC to SCLC is one of the mechanisms underlying drug resistance in NSCLC patients. SCLC-transformed patients show combined characteristics of NSCLC and SCLC; however, they lack timely diagnoses and effective treatment strategies. Thus, we reviewed the clinical characteristics of SCLC transformation patients with a literature search to enhance clinical consciousness, diagnosis, and personalized treatment for patients with it.

scholarly journals Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1615 ◽  
Author(s):  
Jyothi Dhuguru ◽  
Rachid Skouta
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Basic Mechanism ◽  
Small Cell ◽  
Small Cell Lung ◽  
Dna Topoisomerase ◽  
Histone Deacetylase Inhibition ◽  
Lung Cancers ◽  
Drug Candidates

Lung cancer is the leading cause of death in men and women worldwide, affecting millions of people. Between the two types of lung cancers, non-small cell lung cancer (NSCLC) is more common than small cell lung cancer (SCLC). Besides surgery and radiotherapy, chemotherapy is the most important method of treatment for lung cancer. Indole scaffold is considered one of the most privileged scaffolds in heterocyclic chemistry. Indole may serve as an effective probe for the development of new drug candidates against challenging diseases, including lung cancer. In this review, we will focus on discussing the existing indole based pharmacophores in the clinical and pre-clinical stages of development against lung cancer, along with the synthesis of some of the selected anti-lung cancer drugs. Moreover, the basic mechanism of action underlying indole based anti-lung cancer treatment, such as protein kinase inhibition, histone deacetylase inhibition, DNA topoisomerase inhibition, and tubulin inhibition will also be discussed.

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