Small-cell lung cancer in the era of immunotherapy

Majem, Margarita; Rudin, Charles M.

doi:10.21037/tlcr.2017.10.06

Cited by 6 publications

(9 citation statements)

References 20 publications

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“…However, despite having one of the highest mutational burdens, small cell lung cancer (SCLC) is often accompanied by relatively high immunosuppression with low levels of T-cell infi ltration and reduced antigen presentation (9)(10)(11). Consistent with this, clinical trials investigating PD-1 or PD-L1 blockade in patients with SCLC have shown low overall response rates ( 12,13 ).…”

Section: Introductionmentioning

confidence: 95%

Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer

et al. 2019

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Despite recent advances in the use of immunotherapy, only a minority of patients with small cell lung cancer (SCLC) respond to immune checkpoint blockade (ICB). Here, we show that targeting the DNA damage response (DDR) proteins PARP and checkpoint kinase 1 (CHK1) signifi cantly increased protein and surface expression of PD-L1. PARP or CHK1 inhibition remarkably potentiated the antitumor effect of PD-L1 blockade and augmented cytotoxic T-cell infi ltration in multiple immunocompetent SCLC in vivo models. CD8 + T-cell depletion reversed the antitumor effect, demonstrating the role of CD8 + T cells in combined DDR-PD-L1 blockade in SCLC. We further demonstrate that DDR inhibition activated the STING/TBK1/IRF3 innate immune pathway, leading to increased levels of chemokines such as CXCL10 and CCL5 that induced activation and function of cytotoxic T lymphocytes. Knockdown of cGAS and STING successfully reversed the antitumor effect of combined inhibition of DDR and PD-L1. Our results defi ne previously unrecognized innate immune pathway-mediated immunomodulatory functions of DDR proteins and provide a rationale for combining PARP/CHK1 inhibitors and immunotherapies in SCLC. SIGNIFICANCE: Our results defi ne previously unrecognized immunomodulatory functions of DDR inhibitors and suggest that adding PARP or CHK1 inhibitors to ICB may enhance treatment effi cacy in patients with SCLC. Furthermore, our study supports a role of innate immune STING pathway in DDR-mediated antitumor immunity in SCLC.

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Section: Introductionmentioning

confidence: 95%

Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer

et al. 2019

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“…The most common early symptoms in the patients were cough (209, 80.4%), dyspnea (31,11.9%), hoarseness (11,4.2%) and hemoptysis (9, 3.5%), respectively. Moreover, 158 cases (60.8%) had a history of a chronic disease, including 40 (25.3%) patients with ischemic heart disease, 37 (23.4%) with diabetes and 49 (31%) with hypertension.…”

Section: Resultsmentioning

confidence: 99%

“…The average age of the patients at diagnosis was 60.30 (SD=14. 31,, and at the time of death 62.59 (SD=13.71). Moreover, the mean period time from diagnosis to death was 13.36 (SD=12.31) months.…”

Section: Resultsmentioning

confidence: 99%

“…(Table 1) Altogether, 164 (63.1%) and 150 (57.6%) patients had metastasis at the time of study and diagnosis, respectively ( Table 2). The common sites of metastasis were bone (73, 44.5%), brain (60, 36.6%) and liver (31,18.9%), respectively.…”

Section: Resultsmentioning

confidence: 99%

“…, the frequency of different types of lung cancer were 36.9% cases of adenocarcinomas, 14.2% cases of squamous cell carcinoma,9.6% cases of bronchogenic carcinoma and 8.1% cases small cell lung cancer, respectively. There was significant relationship between different types of lung cancerIn the study at Yazd( Iran)(8) 34.9% of patients had SCC and In study at Tehran (23), 19% of patients were SCC(Table 6).According to the results, totally 93 patients (35.7%) had IHC assay reports in which 53 different diagnostic, prognostic, and predictive biomarkers had been measured (Table 5,7).Although all of the measured biomarkers have a diagnostic significance(29)(30)(31)(32)(33)(34), the most relevant biomarkers which have been recently identified, CK20 and CK7, have an important prognostic value in lung cancer patients(35). Moreover, predictive markers like LCA(31) has been checked in a few patients.…”

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confidence: 99%

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Epidemiologic and Histopathologic Feature of Lung Cancer in Central Iran (2012-2018)

Khalilian¹,

Narrei²,

Hadian³

et al. 2020

Preprint

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Background: Lung cancer is one of the common causes of death worldwide.Although the incidence rate of lung cancer in Western countries is decreasing, it presents a growing trend in developed countries. Since there is no accurate enough information about the epidemiological and Histopathologic features of lung cancer in central Iran, Isfahan, we were motivated to conduct this research. Materials and Methods: This was a descriptive, cross-sectional study carried out in central Iran, Isfahan. All demographic, histopathological and clinical data of the lung cancer patients registered in MACSA, a referral charity-based cancer center in central Iran, was analyzed within 2012-2018 using SPSS v.22 software.Results: Altogether 260 patients with lung cancer were included in this study from 6127 cancer patients registered within 2012-2018 (4.2%). Out of them, 66.2% were men, and 18.8 % of the patients were alive at the time of the study. The mean age of the patients at diagnosis was 61.56 (SD=14.11, range: 9-93). Altogether, 63.1% of patients had metastasis of whom 57.6% were in stage IV at diagnosis. The Frequency of different types of lung cancer was 36.9% adenocarcinomas, 14.2% squamous cell Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 8 April 2020 carcinoma, 9.6% bronchogenic carcinoma and 8.1% small cell lung cancer, respectively. Altogether, 128 cases were smokers with an average 35.45 ± 14 packyears. Only in 36.2% of the patients, the diagnostic and therapeutic biomarkers had been checked, and CK7 was positive in 88.9% of the cases in which the biomarker had been checked. Conclusion:Despite to similar Iranian studies, the most common histopathologic type of lung cancer among the patients was adenocarcinoma that it may be attributed to the lower consumption of smoking in our population and their different genetic context. Molecular biomarkers had been checked in a small portion of the patients.More education of the clinicians along with the development of cancer molecular testing may lead to promote the personalized-based approach.

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Effect of Matrix Stiffness and Hepatocyte Growth Factor on Small Cell Lung Cancer Cells in Decellularized Extracellular Matrix‐Based Hydrogels

Han,

2023

Macromolecular Bioscience

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Small cell lung cancer (SCLC) is one of lethal cancers resulting in very low 5‐year‐survival rate. Although its clinical treatment largely relies on chemotherapy, SCLC cell physiology in three‐dimensional matrix has been less explored. In this work, the tumor microenvironment is reconstructed with decellularized porcine pulmonary extracellular matrix (dECM) with hyaluronic acid. To modulate matrix stiffness, the methacrylate groups are introduced into both dECM and hyaluronic acid, followed by photocrosslinking with photoinitiator. The stiffness of the resulting dECM‐based hydrogel covers the stiffness of normal or cancerous tissue with varying dECM content. The proliferation and cancer stem cell marker expression of encapsulated SCLC cells are promoted in a compliant hydrogel matrix, which has a low shear modulus similar to that of the normal tissue. The hepatocyte growth factor (HGF) that induces SCLC cell invasion and chemoresistance markedly increases invasiveness and gene expression levels of CD44 and Sox2 in the hydrogel matrix. In addition, HGF treatment causes higher resistance against anticancer drugs (cisplatin and paclitaxel) in the three‐dimensional microenvironment. These findings indicate that malignant SCLC can be recapitulated in a pulmonary dECM‐based matrix.This article is protected by copyright. All rights reserved

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Small-cell lung cancer in the era of immunotherapy

Cited by 6 publications

References 20 publications

Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer

Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer

Epidemiologic and Histopathologic Feature of Lung Cancer in Central Iran (2012-2018)

Effect of Matrix Stiffness and Hepatocyte Growth Factor on Small Cell Lung Cancer Cells in Decellularized Extracellular Matrix‐Based Hydrogels

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