|
1
|
Greib A, Zhao S, Ploch M, Henricks J, Easterling R, Moodabagil M, Lopez G, Li M, Goodyear EG, Sharp J, Alahmadi A, Kaufman J, Memmott R, He K, Shields P, Carbone DP, Otterson GA, Presley CJ, Wei L, Owen DH, Ho K. Evaluating the effect of immune checkpoint inhibitor treatment on chronic obstructive pulmonary disease in lung cancer patients. Oncoimmunology 2025; 14:2469375. [PMID: 39981683 PMCID: PMC11849934 DOI: 10.1080/2162402x.2025.2469375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 02/10/2025] [Accepted: 02/14/2025] [Indexed: 02/22/2025] Open
Abstract
Immune checkpoint inhibitors (ICIs) are first line treatment for advanced lung cancer. Tobacco use is a shared risk factor for lung cancer and chronic obstructive pulmonary disease (COPD). Although many patients with COPD and lung cancer receive ICIs, the impact of ICIs on COPD is unknown. Here, we evaluated whether ICI treatment was associated with increased COPD disease burden. We conducted a retrospective cohort study of lung cancer patients with and without preexisting COPD who received ICIs from 2011-2021 at The Ohio State University (OSU). For all patients, number of steroid courses and respiratory related hospitalizations were recorded. For those with COPD, COPD medications were collected at and after ICI initiation. Pulmonary function tests, COPD exacerbations, and COPD-related hospitalizations were compared before and after ICI treatment. Linear and generalized mixed models were used to account for potential confounders of worsening COPD. Among 1083 lung cancer patients who received ICIs, 585 (54.0%) had pre-ICI COPD. Patients with COPD were prescribed more COPD medications (3 [1, 4] vs 1 [0, 3], p < 0.001), had more COPD exacerbations (38.3% vs 25.8%, p < 0.001), and more COPD-related hospitalizations (27.9% vs 16.9%, p < 0.001) after ICI initiation compared to before. These findings persisted after multivariable analysis controlling for patients who received chemotherapy or chemoradiation within 12 months of ICI initiation, cancer type, age, BMI, sex, smoking status, type of ICI, and number of ICI doses (p < 0.001). This is a comprehensive study that describes lung cancer patients with COPD treated with ICIs have increased COPD disease burden after ICI initiation.
Collapse
Affiliation(s)
- Anet Greib
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Songzhu Zhao
- Center for Biostatistics, The Ohio State University – James Comprehensive Cancer Center, Columbus, OH, USA
| | - Michelle Ploch
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Jonathan Henricks
- Departments of Internal Medicine and Emergency Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Robert Easterling
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Meghana Moodabagil
- Departments of Internal Medicine and Emergency Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Gabrielle Lopez
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, OH, USA
| | - Mingjia Li
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, OH, USA
| | | | - John Sharp
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, OH, USA
| | - Asrar Alahmadi
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, OH, USA
| | - Jacob Kaufman
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, OH, USA
| | - Regan Memmott
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, OH, USA
| | - Kai He
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, OH, USA
| | - Peter Shields
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, OH, USA
| | - David P. Carbone
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, OH, USA
| | - Gregory A. Otterson
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, OH, USA
| | - Carolyn J. Presley
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, OH, USA
| | - Lai Wei
- Center for Biostatistics, The Ohio State University – James Comprehensive Cancer Center, Columbus, OH, USA
| | - Dwight H. Owen
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, OH, USA
- Pelotonia Institute for Immuno-Oncology, OSUCCC – James, The Ohio State University, Columbus, OH, USA
| | - Kevin Ho
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| |
Collapse
|
|
2
|
Sakai T, Udagawa H, Izumi H, Umemura S, Zenke Y, Matsumoto S, Yoh K, Tomoyuki N, Tokiko N, Taki T, Sakamoto N, Sakashita S, Kojima M, Tsuboi M, Goto K, Ishii G. Clinicopathological Characterization of Squamous Cell Lung Carcinoma Adjacent to Emphysema. Pathol Int 2025. [PMID: 40396431 DOI: 10.1111/pin.70023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 02/25/2025] [Accepted: 05/06/2025] [Indexed: 05/22/2025]
Abstract
The study investigated the clinicopathological features and characteristic immune tumor microenvironment (TME) of lung squamous cell carcinoma (SqCC) adjacent to emphysematous lesions. 184 consecutive patients with peripheral-type SqCC who had undergone complete surgical resection were enrolled. The clinicopathological differences between emphysema-adjacent SqCC (EA-SqCC) and non-emphysema-adjacent SqCC (non-EA-SqCC) were examined. The immune TME, including tumor-infiltrating lymphocytes (TILs) and PD-L1 expression, was also analyzed. EA-SqCC was detected in 132 (71.7%) of the 184 patients. Patients with EA-SqCC had shorter recurrence-free survival (RFS) [median 58.2 months vs. not Reached (NR); hazard ratio (HR) 0.47; 95% CI 0.25-0.81, p < 0.01] and tended to have shorter overall survival (NR vs. NR; HR 0.47; 95% CI 0.27-1.03, p = 0.07) compared to patients with non-EA-SqCC. Evaluation of TILs in the cancer stroma showed the number of Foxp3+ TILs in the EA-SqCC group was significantly higher than that in the non-EA-SqCC group (median number 58 vs. 43, p < 0.01). However, there were no significant differences in the number of CD8 + T cells and the PD-L1 expression between the two groups. Immunosuppressive microenvironment is a characteristic feature of EA-SqCC, which may contribute to the poor prognosis of this disease.
Collapse
Affiliation(s)
- Tetsuya Sakai
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hibiki Udagawa
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroki Izumi
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shigeki Umemura
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yoshitaka Zenke
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shingo Matsumoto
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kiyotaka Yoh
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Naito Tomoyuki
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Nakai Tokiko
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
| | - Tetsuro Taki
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
| | - Naoya Sakamoto
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shingo Sakashita
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
| | - Motohiro Kojima
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masahiro Tsuboi
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Koichi Goto
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Genichiro Ishii
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
- Division of Innovative Pathology and Laboratory Medicine, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| |
Collapse
|
|
3
|
Boudoussier A, Larrouture I, Henrot P, Veillon R, Bardel C, Chautemps C, Caumont C, Schilfarth P, Duruisseaux M, Zysman M. COPD patients with non-small cell lung cancer respond better to anti-PD-(L)1 immune checkpoint inhibitors. Sci Rep 2025; 15:17145. [PMID: 40382449 PMCID: PMC12085620 DOI: 10.1038/s41598-025-02251-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 05/12/2025] [Indexed: 05/20/2025] Open
Abstract
In studies evaluating the efficacy of anti-programmed cell death 1/ligand 1 immune checkpoint inhibitors (anti-PD-(L)1) among patients with non-small cell lung cancer (NSCLC), smokers tend to have better clinical outcomes than non-smokers. However, it is unclear whether NSCLC patients with co-existing chronic obstructive pulmonary disease (COPD) have better clinical outcomes than patients without COPD, regardless of smoking history. The potential correlation of COPD with an improved response to anti-PD-(L)1 was examined in a large cohort of patients with available pulmonary function test results. Patients with stage IV NSCLC who received a minimum of two doses of anti-PD-(L)1 across various treatment lines from 2015 to 2021 were enrolled. Among the 387 patients, pulmonary function test (PFT) data were available for 234 (61%), 139 (59%) of whom had spirometry diagnosed COPD. A retrospective analysis was conducted to evaluate overall survival (OS) and progression-free survival (PFS) based on the presence or absence of COPD. In the univariate analyses, both PFS and OS significantly improved among patients with COPD, compared with patients who did not have COPD (HR 0.71, 95% CI 0.56-0.89 for PFS; HR 0.69, 95% CI 0.52-0.92 for OS), regardless of smoking status. In the multivariate analyses, PFS and OS remained superior among patients with COPD (HR 0.66, 95% CI 0.51-0.85 for PFS; HR 0.63, 95% CI 0.47-0.85 for OS). Additionally, patients with milder COPD (GOLD 1/2 vs. 3/4) had better clinical outcomes than patients with more severe disease. However, neither lung distension (defined as a total lung capacity > 120%) nor pre-COPD status (defined as a diffusing capacity of lung for carbon monoxide < 70%) had a significant impact on PFS or OS. Our study, conducted in the largest cohort with available PFT data to date, showed that COPD was associated with improved survival outcomes among patients with stage IV NSCLC who received anti-PD-(L)1 treatment, regardless of smoking history. The differences were mainly driven by mild and moderate obstruction (GOLD 1 and 2). The dysregulated PD-1/PD-L1 expression that occurs in COPD may offer insights into the different outcomes and thus warrants further investigation.
Collapse
Affiliation(s)
- Augustin Boudoussier
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France
| | | | - Pauline Henrot
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France
- Centre de Recherche cardio-thoracique de Bordeaux, U1045, CIC 1401, Univ-Bordeaux, Pessac, 33604, France
| | - Rémi Veillon
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France
| | - Claire Bardel
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France
| | - Camille Chautemps
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France
| | - Charline Caumont
- Service Biologie des tumeurs, CHU Bordeaux, Pessac, 33604, France
| | - Pierre Schilfarth
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France
| | - Michael Duruisseaux
- Respiratory Department and Early Phase (EPSILYON), Louis Pradel Hospital, Hospices Civils de Lyon Cancer Institute, Lyon, France
- Oncopharmacology Laboratory, Cancer Research Center of Lyon, UMR INSERM 1052 CNRS 5286, Lyon, France
- Université Claude Bernard, Université de Lyon, Lyon, France
| | - Maeva Zysman
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France.
- Centre de Recherche cardio-thoracique de Bordeaux, U1045, CIC 1401, Univ-Bordeaux, Pessac, 33604, France.
| |
Collapse
|
|
4
|
Chan SWS, Pond GR, Goffin JR. The Impact of Chronic Obstructive Pulmonary Disease on Immune Checkpoint Inhibitor Effectiveness in Non-small Cell Lung Cancer: A Population Health Study. J Immunother 2025; 48:138-146. [PMID: 39976181 DOI: 10.1097/cji.0000000000000551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 02/05/2025] [Indexed: 02/21/2025]
Abstract
SUMMARY Chronic obstructive pulmonary disease (COPD) and lung cancer are associated diseases. COPD confers a negative prognosis in NSCLC, but the clinical benefit of immune checkpoint inhibitors (ICI) in this population is unclear. A population-level analysis of patients in Ontario, Canada was performed through the ICES (formerly known as the Institute for Clinical Evaluative Sciences) administrative database. Patients with NSCLC and treated with PD-1/PD-L1 immune checkpoint inhibitors between Jan 2010 and Dec 2020 were included. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using Cox proportional hazards regression. Hospitalizations and duration of treatment were compared secondarily using logistic and linear regression. A total of 4306 patients received ICI and 54% of patients had a diagnosis of COPD. Median (95% CI) OS was 9.2 (8.5-9.9) months for patients with COPD and 8.2 (7.3-8.8) for patients without COPD, which was not significantly different (adjusted hazard ratio (aHR) = 0.94, 95% CI, 0.87-1.01, P = 0.092). Similarly, the median time on treatment was not different (85 vs. 99 days, multivariable P = 0.10). However, the 90-day hospitalization rate was decreased in the COPD population (multivariable odds ratio 0.76, 95% CI 0.62-0.94, P = 0.011). Among patients with NSCLC receiving ICI, our data suggest that a diagnosis of COPD does not result in shortened treatment, poorer survival, or higher rates of hospitalization. COPD itself should not be considered a contraindication to ICI.
Collapse
|
|
5
|
Xiong XF, Zhu M, Wu HX, Wu ZH, Fan LL, Cheng DY. T-cell immune status in patients with acute exacerbation of chronic obstructive pulmonary disease: a case-control study. Front Med (Lausanne) 2025; 12:1433844. [PMID: 39926428 PMCID: PMC11802415 DOI: 10.3389/fmed.2025.1433844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 01/07/2025] [Indexed: 02/11/2025] Open
Abstract
Introduction Immune inflammatory response plays an important role in chronic obstructive pulmonary disease (COPD). However, the cellular immune status of patients with COPD at different phases is unclear. Herein, we aim to investigate the distribution and functional status of T cell subsets in different phases of COPD (acute exacerbation of COPD [AECOPD] and stable COPD [SCOPD]). Methods This is an observational case-control study undertaken in West China Hospital. The distribution of T cell subsets in peripheral blood of AECOPD, SCOPD, and healthy controls (HCs) was measured using multi-color flow cytometry, and the functional status was analyzed by additional staining of activation markers. Results A total of 43 HCs, 43 SCOPD patients, and 64 AECOPD patients were evaluated. The total number and percentage of lymphocytes and the CD4+/CD8+ T cells ratio were significantly lower in AECOPD patients when compared to HCs. HLA-DR expression in CD3+, CD4+, CD8+, CD8+ TCR aβ, and CD4+ TCR aβ T cells was upregulated in the AECOPD group. Similarly, the expressions of HLA-DR, CD57, and PD-1 were higher in T cell subsets in the AECOPD group. Compared with the SCOPD and HC groups, the AECOPD had a significantly lower proportion of CD4+CD27+CD28+ T cells, but opposite results were found for CD4+CD27-CD28- T cells. In addition, the proportion of CD4+CD39+ T cells and CD4+CD25+FoxP3+ T cells was significantly higher in the AECOPD and SCOPD groups when compared to the HC group (P < 0.05). Discussion The distribution of nearly half the T cell subsets in AECOPD patients was significantly different from that in SCOPD patients and HCs. AECOPD patients may have cellular immune suppression, immune dysfunction, abnormal activation, and higher senescence depletion of T cells.
Collapse
Affiliation(s)
- Xiao-feng Xiong
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, China
| | - Min Zhu
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, China
| | - Hong-xia Wu
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Zuo-hong Wu
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Li-li Fan
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - De-yun Cheng
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
6
|
Lycan Jr TW, Norton DL, Ohar JA. COPD and Immune Checkpoint Inhibitors for Cancer: A Literature Review. Int J Chron Obstruct Pulmon Dis 2024; 19:2689-2703. [PMID: 39677829 PMCID: PMC11639883 DOI: 10.2147/copd.s490252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 12/02/2024] [Indexed: 12/17/2024] Open
Abstract
Purpose Immune checkpoint inhibitors are a standard treatment option for many patients with cancer and are most frequently used to treat lung cancer. Chronic obstructive pulmonary disease (COPD) is the most common comorbidity of patients with lung cancer. As the cancer-specific survival of patients with lung cancer continues to increase with modern treatments, it is critical to optimize comorbidities to improve overall survival. This literature review aimed to summarize current research on the impact of COPD upon immunotherapy outcomes. Methods A comprehensive search was conducted in the PubMed database using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Inclusion criteria focused on peer-reviewed articles published between 2010 and 2024 that addressed COPD, cancer, and immune checkpoint inhibitors. The study team screened the studies for relevance and then synthesized them narratively. Results This review identified 37 studies that met the inclusion criteria. Findings suggest that COPD is predictive of improved efficacy but slightly worse toxicity from immune checkpoint inhibitor therapy. The chronic inflammation of COPD leads to immune exhaustion including the overexpression of immune checkpoints on T-cells. Particularly within "hot" tumors that have higher concentrations of tumor-infiltrating lymphocytes, the COPD-related increase in programmed cell death protein 1 (PD-1) signaling likely creates sensitivity to immune checkpoint inhibitors. However, COPD can also lead to respiratory dysfunction, debility, and interstitial lung disease; each of which increases the severity of immune-related adverse events. Conclusion COPD is a critical comorbidity that has a significant impact on many patients with cancer who receive treatment with immune checkpoint inhibitors. Future research is needed to design interventions to optimize COPD care in this high-risk patient population.
Collapse
Affiliation(s)
- Thomas W Lycan Jr
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Dustin L Norton
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Jill A Ohar
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| |
Collapse
|
|
7
|
Velut Y, Arqué B, Wislez M, Blons H, Burroni B, Prieto M, Beau S, Fournel L, Birsen G, Cremer I, Alifano M, Damotte D, Mansuet-Lupo A. The tumor immune microenvironment of SCLC is not associated with its molecular subtypes. Eur J Cancer 2024; 212:115067. [PMID: 39413714 DOI: 10.1016/j.ejca.2024.115067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/28/2024] [Accepted: 10/10/2024] [Indexed: 10/18/2024]
Abstract
INTRODUCTION Small-cell lung carcinoma (SCLC) is a high-grade neuroendocrine carcinoma of poor prognosis. Although immune checkpoint blockers have shown promising results in advanced SCLC, the tumor immune microenvironment (TME) remains poorly understood, with no validated prognostic or predictive biomarkers of efficacy. METHODS This retrospective study included surgically samples from 48 SCLC patients between 2009 and 2018. We assessed the TME using two quantitative 7-plex immunofluorescence panels focusing on T and B cells, and compared it to NSCLC (N = 10). Molecular subtypes were determined by assessing the expression of ASCL1, NEUROD1 and YAP1 using immunohistochemistry. RESULTS Immune-hot SCLC were defined as those exhibiting the highest immune cell and immune-related marker densities. They were associated with longer overall survival, significantly more frequently detected at early stages, and exhibited high PD-L1 expression in immune cells, but were not associated with molecular subtypes. Compared to NSCLC, SCLC had significantly lower densities of CD20 + cells and higher density of PD1 + cells, with no significant differences in CD4 + , CD8 + and plasma cell densities. In univariate analysis, the highest OS was significantly associated with early stage (p < 0.001), low expression of NEUROD1 (p = 0.047), high PD1 + cell density (p < 0.001) and high PD-L1 immune cell expression (p = 0.04). Only stage and PD1 + cell density emerged as independent prognostic markers. CONCLUSION SCLC TME is highly heterogeneous. Immune-hot tumors were associated with OS but not with molecular classification. PD1 expression and PD-L1 expression by immune cells may thus serve as a prognostic marker.
Collapse
Affiliation(s)
- Yoan Velut
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Institut du cancer Paris CARPEM, Team Inflammation, Complement and Cancer, Paris, France
| | - Basilia Arqué
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Institut du cancer Paris CARPEM, Team Inflammation, Complement and Cancer, Paris, France
| | - Marie Wislez
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Institut du cancer Paris CARPEM, Team Inflammation, Complement and Cancer, Paris, France; Department of pneumology, Cochin Hospital, AP-HP.centre, Université Paris Cité, Paris, France
| | - Hélène Blons
- Centre de Recherche des Cordeliers, INSERM CNRS SNC 5096, Sorbonne Université, Université Paris Cité, Institut du cancer Paris CARPEM, Paris, France; Department of Biochemistry, Unit of Pharmacogenetic and Molecular Oncology, Georges Pompidou European Hospital, AP-HP.centre, Université Paris Cité, Paris, France
| | - Barbara Burroni
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Institut du cancer Paris CARPEM, Team Inflammation, Complement and Cancer, Paris, France; Department of Pathology, Cochin Hospital, AP-HP.centre, Université Paris Cité, Paris, France
| | - Mathilde Prieto
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Institut du cancer Paris CARPEM, Team Inflammation, Complement and Cancer, Paris, France; Department of Thoracic Surgery, Cochin Hospital, AP-HP.centre, Université Paris Cité, Paris, France
| | - Siméon Beau
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Institut du cancer Paris CARPEM, Team Inflammation, Complement and Cancer, Paris, France
| | - Ludovic Fournel
- Department of Thoracic Surgery, Cochin Hospital, AP-HP.centre, Université Paris Cité, Paris, France
| | - Gary Birsen
- Department of pneumology, Cochin Hospital, AP-HP.centre, Université Paris Cité, Paris, France
| | - Isabelle Cremer
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Institut du cancer Paris CARPEM, Team Inflammation, Complement and Cancer, Paris, France
| | - Marco Alifano
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Institut du cancer Paris CARPEM, Team Inflammation, Complement and Cancer, Paris, France; Department of Thoracic Surgery, Cochin Hospital, AP-HP.centre, Université Paris Cité, Paris, France
| | - Diane Damotte
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Institut du cancer Paris CARPEM, Team Inflammation, Complement and Cancer, Paris, France; Department of Pathology, Cochin Hospital, AP-HP.centre, Université Paris Cité, Paris, France.
| | - Audrey Mansuet-Lupo
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Institut du cancer Paris CARPEM, Team Inflammation, Complement and Cancer, Paris, France; Department of Pathology, Cochin Hospital, AP-HP.centre, Université Paris Cité, Paris, France
| |
Collapse
|
|
8
|
Bortolot M, Cortiula F, Fasola G, De Ruysscher D, Naidoo J, Hendriks LEL. Treatment of unresectable stage III non-small cell lung cancer for patients who are under-represented in clinical trials. Cancer Treat Rev 2024; 129:102797. [PMID: 38972134 DOI: 10.1016/j.ctrv.2024.102797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 06/27/2024] [Accepted: 07/02/2024] [Indexed: 07/09/2024]
Abstract
Concurrent chemoradiotherapy (cCRT) followed by one year of consolidation durvalumab is the current standard-of-care for patients with unresectable stage III non-small cell lung cancer (NSCLC), of good functional status. However, cCRT and consolidation durvalumab may be challenging to administer for selected patient populations underrepresented or even excluded in clinical trials: older and/or frail patients; those with cardiovascular or respiratory comorbidities in which treatment-related adverse events may be higher, and patients with pre-existing autoimmune disorders for whom immunotherapy use is controversial. In this narrative review, we discuss the current evidence, challenges, ongoing clinical trials and potential future treatment scenarios in relevant subgroups of patients with locally advanced NSCLC, who are underrepresented in clinical trials.
Collapse
Affiliation(s)
- Martina Bortolot
- University of Udine, Department of Medicine (DAME), Udine, Italy; University Hospital of Udine, Department of Oncology, Udine, Italy
| | - Francesco Cortiula
- University Hospital of Udine, Department of Oncology, Udine, Italy; Department of Radiation Oncology (Maastro), Maastricht University Medical Centre (+), GROW School for Oncology and Reproduction, Maastricht, the Netherlands.
| | - Gianpiero Fasola
- University Hospital of Udine, Department of Oncology, Udine, Italy
| | - Dirk De Ruysscher
- Department of Radiation Oncology (Maastro), Maastricht University Medical Centre (+), GROW School for Oncology and Reproduction, Maastricht, the Netherlands
| | - Jarushka Naidoo
- Beaumont Hospital and RCSI University of Health Sciences, Dublin, Ireland; Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins University, Baltimore, USA
| | - Lizza E L Hendriks
- Department of Pulmonary Diseases, Maastricht University Medical Centre (+), GROW School for Oncology and Reproduction, Maastricht, the Netherlands
| |
Collapse
|
|
9
|
Lunardi F, Nardo G, Lazzarini E, Tzorakoleftheraki SE, Comacchio GM, Fonzi E, Tebaldi M, Vedovelli L, Pezzuto F, Fortarezza F, Schiavon M, Rea F, Indraccolo S, Calabrese F. Is There a Link between Chronic Obstructive Pulmonary Disease and Lung Adenocarcinoma? A Clinico-Pathological and Molecular Study. J Pers Med 2024; 14:839. [PMID: 39202030 PMCID: PMC11355616 DOI: 10.3390/jpm14080839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/03/2024] [Accepted: 08/06/2024] [Indexed: 09/03/2024] Open
Abstract
Chronic Obstructive Pulmonary Disease (COPD) and lung cancer are strictly related. To date, it is unknown if COPD-associated cancers are different from the tumors of non-COPD patients. The main goal of the study was to compare the morphological/molecular profiles of lung adenocarcinoma (LUAD) samples of COPD, non-COPD/smokers and non-COPD/non-smokers, and to investigate if a genetic instability also characterized non-pathological areas. This study included 110 patients undergoing surgery for a LUAD, divided into three groups: COPD/smoker LUAD (38), non-COPD/smoker LUAD (54) and non-COPD/non-smoker LUAD (18). The tissue samples were systemically evaluated by pathologists and analyzed using a 30-gene Next Generation Sequencing (NGS) panel. In a subset of patients, tissues taken far from the neoplasia were also included. The non-COPD/smoker LUAD were characterized by a higher proliferative index (p = 0.001), while the non-COPD/non-smoker LUAD showed higher percentages of lepidic pattern (p = 0.008), lower necrosis, higher fibrosis, and a significantly lower mutation rate in the KRAS and PIK3CA genes. Interestingly, the same gene mutations were found in pathological and normal areas exclusively in the COPD/smokers and non-COPD/smokers. COPD/smoker LUAD seem to be similar to non-COPD/smoker LUAD, particularly for the genetic background. A less aggressive cancer phenotype was confirmed in non-COPD/non-smokers. The genetic alterations detected in normal lungs from smokers with and without COPD reinforce the importance of screening to detect early neoplastic lesions.
Collapse
Affiliation(s)
- Francesca Lunardi
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy; (F.L.); (G.M.C.); (L.V.); (F.P.); (F.F.); (M.S.); (F.R.)
| | - Giorgia Nardo
- Basic and Translational Oncology Unit, Istituto Oncologico Veneto IOV—IRCCS, 35128 Padova, Italy; (G.N.); (E.L.); (S.I.)
| | - Elisabetta Lazzarini
- Basic and Translational Oncology Unit, Istituto Oncologico Veneto IOV—IRCCS, 35128 Padova, Italy; (G.N.); (E.L.); (S.I.)
| | | | - Giovanni Maria Comacchio
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy; (F.L.); (G.M.C.); (L.V.); (F.P.); (F.F.); (M.S.); (F.R.)
| | - Eugenio Fonzi
- IRCCS Istituto Tumori “Dino Amadori” IRST, 47014 Meldola, Italy; (E.F.); (M.T.)
| | - Michela Tebaldi
- IRCCS Istituto Tumori “Dino Amadori” IRST, 47014 Meldola, Italy; (E.F.); (M.T.)
| | - Luca Vedovelli
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy; (F.L.); (G.M.C.); (L.V.); (F.P.); (F.F.); (M.S.); (F.R.)
| | - Federica Pezzuto
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy; (F.L.); (G.M.C.); (L.V.); (F.P.); (F.F.); (M.S.); (F.R.)
| | - Francesco Fortarezza
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy; (F.L.); (G.M.C.); (L.V.); (F.P.); (F.F.); (M.S.); (F.R.)
| | - Marco Schiavon
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy; (F.L.); (G.M.C.); (L.V.); (F.P.); (F.F.); (M.S.); (F.R.)
| | - Federico Rea
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy; (F.L.); (G.M.C.); (L.V.); (F.P.); (F.F.); (M.S.); (F.R.)
| | - Stefano Indraccolo
- Basic and Translational Oncology Unit, Istituto Oncologico Veneto IOV—IRCCS, 35128 Padova, Italy; (G.N.); (E.L.); (S.I.)
- Department of Surgery Oncology and Gastroenterology, University of Padova, 35124 Padova, Italy
| | - Fiorella Calabrese
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy; (F.L.); (G.M.C.); (L.V.); (F.P.); (F.F.); (M.S.); (F.R.)
| |
Collapse
|
|
10
|
Kang Q, He L, Zhang Y, Zhong Z, Tan W. Immune-inflammatory modulation by natural products derived from edible and medicinal herbs used in Chinese classical prescriptions. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155684. [PMID: 38788391 DOI: 10.1016/j.phymed.2024.155684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/29/2024] [Accepted: 04/24/2024] [Indexed: 05/26/2024]
Abstract
BACKGROUND Edible and medicinal herbs1 (EMHs) refer to a class of substances with dual attribution of food and medicine. These substances are traditionally used as food and also listed in many international pharmacopoeias, including the European Pharmacopoeia, the United States Pharmacopoeia, and the Chinese Pharmacopoeia. Some classical formulas that are widely used in traditional Chinese medicine include a series of EMHs, which have been shown to be effective with obvious characteristics and advantages. Notably, these EMHs and Chinese classical prescriptions2 (CCPs) have also attracted attention in international herbal medicine research because of their low toxicity and high efficiency as well as the rich body of experience for their long-term clinical use. PURPOSE Our purpose is to explore the potential therapeutic effect of EMHs with immune-inflammatory modulation for the study of modern cancer drugs. STUDY DESIGN In the present study, we present a detailed account of some EMHs used in CCPs that have shown considerable research potential in studies exploring modern drugs with immune-inflammatory modulation. METHODS Approximately 500 publications in the past 30 years were collected from PubMed, Web of Science and ScienceDirect using the keywords, such as natural products, edible and medicinal herbs, Chinese medicine, classical prescription, immune-inflammatory, tumor microenvironment and some related synonyms. The active ingredients instead of herbal extracts or botanical mixtures were focused on and the research conducted over the past decade were discussed emphatically and analyzed comprehensively. RESULTS More than ten natural products derived from EMHs used in CCPs are discussed and their immune-inflammatory modulation activities, including enhancing antitumor immunity, regulating inflammatory signaling pathways, lowering the proportion of immunosuppressive cells, inhibiting the secretion of proinflammatory cytokines, immunosuppressive factors, and inflammatory mediators, are summarized. CONCLUSION Our findings demonstrate the immune-inflammatory modulating role of those EMHs used in CCPs and provide new ideas for cancer treatment in clinical settings.
Collapse
Affiliation(s)
- Qianming Kang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Luying He
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Yang Zhang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Zhangfeng Zhong
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China.
| | - Wen Tan
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
| |
Collapse
|
|
11
|
Xue H, Lan X, Xue T, Tang X, Yang H, Hu Z, Xu N, Xie B. PD-1 + T lymphocyte proportions and hospitalized exacerbation of COPD: a prospective cohort study. Respir Res 2024; 25:218. [PMID: 38789950 PMCID: PMC11127417 DOI: 10.1186/s12931-024-02847-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
OBJECTIVE To evaluate the predictive value of PD-1 expression in T lymphocytes for rehospitalization due to acute exacerbations of COPD (AECOPD) in discharged patients. METHODS 115 participants hospitalized with COPD (average age 71.8 ± 6.0 years) were recruited at Fujian Provincial Hospital. PD1+T lymphocytes proportions (PD1+T%), baseline demographics and clinical data were recorded at hospital discharge. AECOPD re-admission were collected at 1-year follow-up. Kaplan-Meier analysis compared the time to AECOPD readmissions among groups stratified by PD1+T%. Multivariable Cox proportional hazards regression and stratified analysis determined the correlation between PD1+T%, potential confounders, and AECOPD re-admission. ROC and DCA evaluated PD1+T% in enhancing the clinical predictive values of Cox models, BODE and CODEX. RESULTS 68 participants (59.1%) were AECOPD readmitted, those with AECOPD readmission exhibited significantly elevated baseline PD-1+CD4+T/CD4+T% and PD-1+CD8 + T/CD8 + T% compared to non-readmitted counterparts. PD1+ T lymphocyte levels statistically correlated with BODE and CODEX indices. Kaplan-Meier analysis demonstrated that those in Higher PD1+ T lymphocyte proportions had reduced time to AECOPD readmission (logRank p < 0.05). Cox analysis identified high PD1+CD4+T and PD1+CD8+T ratios as risk factors of AECOPD readmission, with hazard ratios of 1.384(95%CI [1.043-1.725]) and 1.401(95%CI [1.013-1.789]), respectively. Notably, in patients aged < 70 years and with fewer than twice AECOPD episodes in the previous year, high PD1+T lymphocyte counts significantly increased risk for AECOPD readmission(p < 0.05). The AECOPD readmission predictive model, incorporating PD1+T% exhibited superior discrimination to the Cox model, BODE index and CODEX index, AUC of ROC were 0.763(95%CI [0.633-0.893]) and 0.734(95%CI [0.570-0.899]) (DeLong's test p < 0.05).The DCA illustrates that integrating PD1+T% into models significantly enhances the utility in aiding clinical decision-making. CONCLUSION Evaluation of PD1+ lymphocyte proportions offer a novel perspective for identifying high-risk COPD patients, potentially providing insights for COPD management. TRIAL REGISTRATION Chinese Clinical Trial Registry (ChiCTR, URL: www.chictr.org.cn/ ), Registration number: ChiCTR2200055611 Date of Registration: 2022-01-14.
Collapse
Affiliation(s)
- Hong Xue
- Department of Respiratory and Critical Care Medicine, Provincial School of Clinical Medicine, Fujian Provincial Hospital, Fujian Medical University, No.134 East Street, Fuzhou, Fujian, 350001, China
| | - Xiuyan Lan
- Department of Respiratory and Critical Care Medicine, Provincial School of Clinical Medicine, Fujian Provincial Hospital, Fujian Medical University, No.134 East Street, Fuzhou, Fujian, 350001, China
| | - Ting Xue
- Center of Health Management, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, 350001, China
| | - Xuwei Tang
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, 1 Xuefu north Road, Fuzhou, 350122, China
| | - Haitao Yang
- Department of Respiratory and Critical Care Medicine, Provincial School of Clinical Medicine, Fujian Provincial Hospital, Fujian Medical University, No.134 East Street, Fuzhou, Fujian, 350001, China
| | - Zhijian Hu
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, 1 Xuefu north Road, Fuzhou, 350122, China
| | - Nengluan Xu
- Department of Infectious Diseases, Provincial School of Clinical Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, No.516 Jinrong South Street, Fuzhou, Fujian, 350001, China.
| | - Baosong Xie
- Department of Respiratory and Critical Care Medicine, Provincial School of Clinical Medicine, Fujian Provincial Hospital, Fujian Medical University, No.134 East Street, Fuzhou, Fujian, 350001, China.
| |
Collapse
|
|
12
|
Zeng A, Yin Y, Xu Z, Abuduwayiti A, Yang F, Shaik MS, Wang C, Chen K, Wang C, Fang X, Dai J. Down-regulated HHLA2 enhances neoadjuvant immunotherapy efficacy in patients with non-small cell lung cancer (NSCLC) with chronic obstructive pulmonary disease (COPD). BMC Cancer 2024; 24:396. [PMID: 38553708 PMCID: PMC10979619 DOI: 10.1186/s12885-024-12137-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 03/17/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND Emerging data suggested a favorable outcome in advanced non-small cell lung cancer (NSCLC) with chronic obstructive pulmonary disease (COPD) patients treated by immunotherapy. The objective of this study was to investigate the effectiveness of neoadjuvant immunotherapy among NSCLC with COPD versus NSCLC without COPD and explore the potential mechanistic links. PATIENTS AND METHODS Patients with NSCLC receiving neoadjuvant immunotherapy and surgery at Shanghai Pulmonary Hospital between November 2020 and January 2023 were reviewed. The assessment of neoadjuvant immunotherapy's effectiveness was conducted based on the major pathologic response (MPR). The gene expression profile was investigated by RNA sequencing data. Immune cell proportions were examined using flow cytometry. The association between gene expression, immune cells, and pathologic response was validated by immunohistochemistry and single-cell data. RESULTS A total of 230 NSCLC patients who received neoadjuvant immunotherapy were analyzed, including 60 (26.1%) with COPD. Multivariate logistic regression demonstrated that COPD was a predictor for MPR after neoadjuvant immunotherapy [odds ratio (OR), 2.490; 95% confidence interval (CI), 1.295-4.912; P = 0.007]. NSCLC with COPD showed a down-regulation of HERV-H LTR-associating protein 2 (HHLA2), which was an immune checkpoint molecule, and the HHLA2low group demonstrated the enrichment of CD8+CD103+ tissue-resident memory T cells (TRM) compared to the HHLA2high group (11.9% vs. 4.2%, P = 0.013). Single-cell analysis revealed TRM enrichment in the MPR group. Similarly, NSCLC with COPD exhibited a higher proportion of CD8+CD103+TRM compared to NSCLC without COPD (11.9% vs. 4.6%, P = 0.040). CONCLUSIONS The study identified NSCLC with COPD as a favorable lung cancer type for neoadjuvant immunotherapy, offering a new perspective on the multimodality treatment of this patient population. Down-regulated HHLA2 in NSCLC with COPD might improve the MPR rate to neoadjuvant immunotherapy owing to the enrichment of CD8+CD103+TRM. TRIAL REGISTRATION Approval for the collection and utilization of clinical samples was granted by the Ethics Committee of Shanghai Pulmonary Hospital (Approval number: K23-228).
Collapse
Affiliation(s)
- Ao Zeng
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 200433, Shanghai, China
| | - Yanze Yin
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 200433, Shanghai, China
| | - Zhilong Xu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 200433, Shanghai, China
| | - Abudumijiti Abuduwayiti
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 200433, Shanghai, China
| | - Fujun Yang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 200433, Shanghai, China
| | | | - Chao Wang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 200433, Shanghai, China
| | - Keyi Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 200433, Shanghai, China
| | - Chao Wang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 200433, Shanghai, China
| | - Xinyun Fang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 200433, Shanghai, China
| | - Jie Dai
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 200433, Shanghai, China.
| |
Collapse
|
|
13
|
Riondino S, Rosenfeld R, Formica V, Morelli C, Parisi G, Torino F, Mariotti S, Roselli M. Effectiveness of Immunotherapy in Non-Small Cell Lung Cancer Patients with a Diagnosis of COPD: Is This a Hidden Prognosticator for Survival and a Risk Factor for Immune-Related Adverse Events? Cancers (Basel) 2024; 16:1251. [PMID: 38610929 PMCID: PMC11011072 DOI: 10.3390/cancers16071251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
The interplay between the immune system and chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC) is complex and multifaceted. In COPD, chronic inflammation and oxidative stress can lead to immune dysfunction that can exacerbate lung damage, further worsening the respiratory symptoms. In NSCLC, immune cells can recognise and attack the cancer cells, which, however, can evade or suppress the immune response by various mechanisms, such as expressing immune checkpoint proteins or secreting immunosuppressive cytokines, thus creating an immunosuppressive tumour microenvironment that promotes cancer progression and metastasis. The interaction between COPD and NSCLC further complicates the immune response. In patients with both diseases, COPD can impair the immune response against cancer cells by reducing or suppressing the activity of immune cells, or altering their cytokine profile. Moreover, anti-cancer treatments can also affect the immune system and worsen COPD symptoms by causing lung inflammation and fibrosis. Immunotherapy itself can also cause immune-related adverse events that could worsen the respiratory symptoms in patients with COPD-compromised lungs. In the present review, we tried to understand the interplay between the two pathologies and how the efficacy of immunotherapy in NSCLC patients with COPD is affected in these patients.
Collapse
|
|
14
|
Dong W, Yin Y, Liu B, Jiang Y, Wang L, Shi D, Qin J. Efficacy and safety of pembrolizumab as first-line treatment for advanced non-small cell lung cancer complicated with chronic obstructive pulmonary disease: protocol for a prospective, single-arm, single-center, phase II clinical trial. Front Oncol 2024; 14:1179232. [PMID: 38515570 PMCID: PMC10955356 DOI: 10.3389/fonc.2024.1179232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 02/27/2024] [Indexed: 03/23/2024] Open
Abstract
Background The first-line standard treatment option for patients with NSCLC complicated with Chronic obstructive pulmonary disease (COPD) is still unclear and relies on the treatment option of NSCLC alone. To date, a limited number of retrospective studies have explored the efficacy and safety of immunotherapy in patients with NSCLC complicated with COPD. We therefore designed this study to further explore the efficacy and safety of first-line immunotherapy in patients with NSCLC complicated with COPD. Methods This study was designed as a single-armed, single-center, prospective, phase II clinical study. It will include 30 advanced (stage IV) NSCLC combined with COPD primary treatment subjects. Each subject's diagnosis will be confirmed by clinical, radiographic, pathologic, and pulmonary function evaluation. A fixed dose of 200 mg pembrolizumab will be administered by intravenous infusion on day1 every 3 weeks (Q3W). The management of stable and acute exacerbations of COPD include home oxygen therapy, and the use of conventional medications are also administered. Imaging evaluation will be performed every 6 weeks for 6 months from the first pembrolizumab dose and approximately every 12 weeks thereafter until disease progression or early withdrawal. COPD status will be evaluated every 3 months by pulmonary function, GOLD grading, mMRC score, CAT score, ABCD grouping, and AECOPD severity. The primary outcome is Progression-free survival. The secondary outcome measures include objective response rate, overall survival, rate of acute exacerbations of COPD (times/year), lung function, mMRC score, CAT score, impact of treatment on patient's health-related quality of life, antibiotic use (including duration and classes), and adverse events associated with immune checkpoint inhibitors. Exploratory endpoint is to explore the association between COPD grade and the degree of immune cell (CD4+ T lymphocytes and CD8+ T lymphocytes) infiltration, as well as the association between COPD grade and the efficacy of immune checkpoint inhibitors. Clinical trial registration ClinicalTrials.gov, identifier NCT05578222.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Jianwen Qin
- Department of Respiratory and Critica Care Medicine, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China
| |
Collapse
|
|
15
|
Yin Y, Zeng A, Abuduwayiti A, Xu Z, Chen K, Wang C, Fang X, Wang J, Jiang G, Dai J. MAIT cells are associated with responsiveness to neoadjuvant immunotherapy in COPD-associated NSCLC. Cancer Med 2024; 13:e7112. [PMID: 38509769 PMCID: PMC10955227 DOI: 10.1002/cam4.7112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/29/2024] [Accepted: 03/04/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND Patients with non-small cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD) experience worse clinical outcomes but respond better to immunotherapy than patients with NSCLC without COPD. Mucosal-associated invariant T (MAIT) cells, a versatile population of innate immune T lymphocytes, have a crucial function in the response to infection and tumors. This study investigated the distribution of MAIT cells in COPD-associated NSCLC and their involvement in the immune response. METHODS Flow cytometry, immunohistochemistry, and immunofluorescence were performed on tissue samples of patients with NSCLC, with or without COPD, treated with or without anti-programmed death 1 (PD1) immunotherapy. MAIT cells were stimulated with 5-OP-RU using a mouse subcutaneous tumor model. RESULTS Tumors contained significantly more MAIT cells than paraneoplastic tissues, and CD8+ MAIT cells accounted for more than 90% of these cells. Patients with NSCLC and COPD had higher CD8+ MAIT cell counts than those with NSCLC without COPD. Additionally, patients with NSCLC and COPD displayed reduced expression of the activation marker, CD69, and functional markers, granzyme B (GZMB) and interferon γ (IFNγ), and higher expression of the immune exhaustion marker, PD1. Among patients who received immunotherapy, the proportion with a complete or partial response was higher in those with COPD than in those without COPD. In patients with NSCLC and COPD, the major pathologic response (MPR) group had higher MAIT levels than those in the no major pathologic response (NPR) group. In the mouse subcutaneous tumor model stimulation of MAIT cells using 5-OP-RU enhanced the antitumor effects of anti-PD1. CONCLUSIONS In patients with NSCLC and COPD, response to immunotherapy is associated with accumulation of CD8+ MAIT cells showing immune exhaustion. These findings may contribute to innovative approaches for immunotherapy targeting CD8+ MAIT cells.
Collapse
Affiliation(s)
- Yanze Yin
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Ao Zeng
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Abudumijiti Abuduwayiti
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Zhilong Xu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Keyi Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Chao Wang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Xinyun Fang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Jiarui Wang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Gening Jiang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Jie Dai
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of MedicineTongji UniversityShanghaiChina
| |
Collapse
|
|
16
|
Dong W, Yin Y, Yang S, Liu B, Chen X, Wang L, Su Y, Jiang Y, Shi D, Sun D, Qin J. Impact of chronic obstructive pulmonary disease on the efficacy and safety of neoadjuvant immune checkpoint inhibitors combined with chemotherapy for resectable non-small cell lung cancer: a retrospective cohort study. BMC Cancer 2024; 24:153. [PMID: 38291354 PMCID: PMC10829328 DOI: 10.1186/s12885-024-11902-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 01/20/2024] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Neoadjuvant immune checkpoint inhibitors(ICIs) combined with chemotherapy can improve non-small cell lung cancer(NSCLC) patients' pathological responses and show promising improvements in survival. Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease, and its associated abnormal inflammatory response affects not only the immunotherapy efficacy but also immune-related adverse events. It remains unclear whether NSCLC patients with COPD can benefit from neoadjuvant ICIs combined with chemotherapy. METHODS A retrospective observational clinical study was conducted on 105 consecutive NSCLC patients receiving neoadjuvant ICIs combined with chemotherapy at the Department of Thoracic Surgery of Tianjin Chest Hospital between April 2020 and April 2023. RESULTS A total of 74 NSCLC patients were included in the study, including 30 patients with COPD and 44 patients without COPD. The percentage of patients with a pathological complete response (PCR) was higher in the COPD group than in the non-COPD group (43.3% vs. 20.5%, P = 0.042). Multivariate logistic regression analysis of factors associated with PCR showed that the adjusted odds ratio (OR) was statistically significant for presence of COPD (OR = 3.020, 95%CI: 1.042-8.757; P = 0.042). Major pathological response (66.7% vs. 50%, P = 0.155), R0 resection rate (96.7% vs.93.2%, P = 0.642), N2 lymph node downstaging(92.3% vs. 66.7%, P = 0.182) and objective response rate (70% vs. 63.6%, P = 0.57) were not significantly different between the groups. Progression-free survival(PFS) was not reached in the COPD group and 17 months (95%CI: 12.1-21.9) in the non-COPD group, with statistically significance (χ2 = 6.247, P = 0.012). Multivariate Cox's regression analysis showed that the adjusted hazard ratio (HRadj) was statistically significant for presence of COPD (HRadj = 0.321, 95%CI: 0.111-0.930; P = 0.036). The grade 3 and grade 4 adverse events in the COPD group were leukopenia (3.3%, 6.7%), neutropenia (3.3%, 6.7%), fatigue (6.7%, 0%), gastrointestinal reactions (3.3%, 0%), and hypothyroidism (3.3%, 0%). In the non-COPD group, the corresponding adverse events were leukopenia (6.8%, 6.8%), neutropenia (3.3%, 6.8%), fatigue (2.3%, 0%), gastrointestinal reactions (2.3%, 0%), and hypothyroidism (2.3%, 0%), respectively. CONCLUSIONS The present study indicates that the presence of COPD may improve PCR, prolong PFS, and have an acceptable safety profile in NSCLC patients receiving neoadjuvant ICIs combined with chemotherapy.
Collapse
Affiliation(s)
- Weigang Dong
- Department of Respiratory and Critica Care Medicine, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China
| | - Yan Yin
- Department of Respiratory and Critica Care Medicine, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China
| | - Shengnan Yang
- Department of Respiratory and Critica Care Medicine, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China
| | - Bin Liu
- Department of Respiratory and Critica Care Medicine, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China
| | - Xi Chen
- Department of Respiratory and Critica Care Medicine, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China
| | - Lina Wang
- Department of Respiratory and Critica Care Medicine, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China
| | - Yue Su
- Department of Respiratory and Critica Care Medicine, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China
| | - Yan Jiang
- Department of Respiratory and Critica Care Medicine, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China
| | - Dongsheng Shi
- Department of Respiratory and Critica Care Medicine, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China
| | - Daqiang Sun
- Department of Thoracic Surgery, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China.
| | - Jianwen Qin
- Department of Respiratory and Critica Care Medicine, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China.
| |
Collapse
|
|
17
|
Mariniello DF, D’Agnano V, Cennamo D, Conte S, Quarcio G, Notizia L, Pagliaro R, Schiattarella A, Salvi R, Bianco A, Perrotta F. Comorbidities in COPD: Current and Future Treatment Challenges. J Clin Med 2024; 13:743. [PMID: 38337438 PMCID: PMC10856710 DOI: 10.3390/jcm13030743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/24/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition, primarily characterized by the presence of a limited airflow, due to abnormalities of the airways and/or alveoli, that often coexists with other chronic diseases such as lung cancer, cardiovascular diseases, and metabolic disorders. Comorbidities are known to pose a challenge in the assessment and effective management of COPD and are also acknowledged to have an important health and economic burden. Local and systemic inflammation have been proposed as having a potential role in explaining the association between COPD and these comorbidities. Considering that the number of patients with COPD is expected to rise, understanding the mechanisms linking COPD with its comorbidities may help to identify new targets for therapeutic purposes based on multi-dimensional assessments.
Collapse
Affiliation(s)
- Domenica Francesca Mariniello
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (D.F.M.); (V.D.); (D.C.); (S.C.); (G.Q.); (L.N.); (R.P.); (A.S.); (A.B.)
| | - Vito D’Agnano
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (D.F.M.); (V.D.); (D.C.); (S.C.); (G.Q.); (L.N.); (R.P.); (A.S.); (A.B.)
| | - Donatella Cennamo
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (D.F.M.); (V.D.); (D.C.); (S.C.); (G.Q.); (L.N.); (R.P.); (A.S.); (A.B.)
| | - Stefano Conte
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (D.F.M.); (V.D.); (D.C.); (S.C.); (G.Q.); (L.N.); (R.P.); (A.S.); (A.B.)
| | - Gianluca Quarcio
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (D.F.M.); (V.D.); (D.C.); (S.C.); (G.Q.); (L.N.); (R.P.); (A.S.); (A.B.)
| | - Luca Notizia
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (D.F.M.); (V.D.); (D.C.); (S.C.); (G.Q.); (L.N.); (R.P.); (A.S.); (A.B.)
| | - Raffaella Pagliaro
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (D.F.M.); (V.D.); (D.C.); (S.C.); (G.Q.); (L.N.); (R.P.); (A.S.); (A.B.)
| | - Angela Schiattarella
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (D.F.M.); (V.D.); (D.C.); (S.C.); (G.Q.); (L.N.); (R.P.); (A.S.); (A.B.)
| | - Rosario Salvi
- U.O.C. Chirurgia Toracica, Azienda Ospedaliera “S.G. Moscati”, 83100 Avellino, Italy;
| | - Andrea Bianco
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (D.F.M.); (V.D.); (D.C.); (S.C.); (G.Q.); (L.N.); (R.P.); (A.S.); (A.B.)
| | - Fabio Perrotta
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (D.F.M.); (V.D.); (D.C.); (S.C.); (G.Q.); (L.N.); (R.P.); (A.S.); (A.B.)
| |
Collapse
|
|
18
|
Wang F, Deng G, Liang N, Hu P, Liu K, Liu T, Li Y, Yuan M, Liu L, Xie J, Qiao L, Liu F, Zhang J. Serum ferritin level is an effective prognostic factor for lung cancer immunotherapy. Cancer Biol Ther 2023; 24:2285367. [PMID: 38031846 PMCID: PMC10783829 DOI: 10.1080/15384047.2023.2285367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 11/15/2023] [Indexed: 12/01/2023] Open
Abstract
Immunotherapy of lung cancer has achieved promising clinical results. However, it is urgent to develop predictive biomarkers for effective immunotherapy. While ferroptosis plays a critical role in immunotherapy efficacy, ferritin is an important regulatory factor. We, therefore, hypothesize that basal serum ferritin levels before immunotherapy and their corresponding changes during immunotherapy can be useful predictors of immunotherapy response in patients with lung cancer. We measured serum ferritin levels in 107 patients with lung cancer before and during immune checkpoint blockade treatments and studied the correlation between ferritin levels, response rate, and survival. Moreover, the correlation between basal ferritin and PD-L1 expression, tumor stages and pathological types was also analyzed. Patients with lower basal serum ferritin levels before immunotherapy had longer progression-free survival (PFS) (median 7 vs 4 months, P = .023) and higher disease control rate (DCR) (X2 = 4.837, P = .028), those with downregulated serum ferritin levels during immunotherapy correlated with longer PFS (median 9.5 vs 4 months, P < .001) and higher DCR (X2 = 6.475, P = .011). However, the "integrated factor", which was calculated as the combination of lower basal serum ferritin levels before immunotherapy and downregulated serum ferritin levels during immunotherapy, correlated with prolonged PFS (P < .001). Multivariate analyses revealed that the basal serum ferritin levels before immunotherapy and the corresponding changes during immunotherapy were both strong independent prognostic factors (hazard ratio (HR) = 1.60, P = .041; HR = 2.65, P = .001). These findings suggest that serum ferritin levels can be used as a prognostic biomarker for lung cancer in predicting immunotherapy efficacy.
Collapse
Affiliation(s)
- Fei Wang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- Department of Oncology, Zaozhuang Shizhong District People’s Hospital, Zaozhuang, China
| | - Guodong Deng
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Ning Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Pingping Hu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Kuo Liu
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Tong Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China
| | - Yang Li
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Meng Yuan
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, Shandong Provincial Qianfoshan Hospital, Weifang Medical University, Jinan, China
| | - Li Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China
| | - Jian Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Lili Qiao
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Fengjun Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Jiandong Zhang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- Department of Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China
| |
Collapse
|
|
19
|
Liu X, Zhang L, Zhu B, Liu Y, Li L, Hou J, Qian M, Zheng N, Zeng Y, Chen C, Goel A, Wang X. Role of GSDM family members in airway epithelial cells of lung diseases: a systematic and comprehensive transcriptomic analysis. Cell Biol Toxicol 2023; 39:2743-2760. [PMID: 37462807 DOI: 10.1007/s10565-023-09799-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 03/05/2023] [Indexed: 12/03/2023]
Abstract
Gasdermin (GSDM) family, the key executioners of pyroptosis, play crucial roles in anti-pathogen and anti-tumor immunities, although little is known about the expression of GSDM in lung diseases at single-cell resolution, especially in lung epithelial cells. We comprehensively investigated the transcriptomic profiles of GSDM members in various lung tissues from healthy subjects or patients with different lung diseases at single cell level, e.g., chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), lung adenocarcinoma (LUAD), or systemic sclerosis (SSC). The expression of GSDM members varied among pulmonary cell types (immune cells, structural cells, and especially epithelial cells) and even across lung diseases. Regarding disease-associated specificities, we found that GSDMC or GSDMD altered significantly in ciliated epithelia of COPD or LUAD, GSDMD in mucous, club, and basal cells of LUAD and GSDMC in mucous epithelia of para-tumor tissue, as compared with the corresponding epithelia of other diseases. The phenomic specificity of GSDM in lung cancer subtypes was noticed by comparing with 15 non-pulmonary cancers and para-cancer samples. GSDM family gene expression changes were also observed in different lung epithelial cell lines (e.g., HBE, A549, H1299, SPC-1, or H460) in responses to external challenges, including lipopolysaccharide (LPS), lysophosphatidylcholine (lysoPC), cigarette smoking extract (CSE), cholesterol, and AR2 inhibitor at various doses or durations. GSDMA is rarely expressed in those cell lines, while GSDMB and GSDMC are significantly upregulated in human lung epithelia. Our data indicated that the heterogeneity of GSDM member expression exists at different cells, pathologic conditions, challenges, probably dependent upon cell biological phenomes, functions, and behaviors, upon cellular responses to external changes, and the nature and severity of lung disease. Thus, the deep exploration of GSDM phenomes may provide new insights into understanding the single-cell roles in the tissue, regulatory roles of the GSDM family in the pathogenesis, and potential values of biomarker identification and development.
Collapse
Affiliation(s)
- Xuanqi Liu
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University Shanghai Medical College, Shanghai, China
- Shanghai Institute of Clinical Bioinformatics, Shanghai, China
- Shanghai Engineering Research for AI Technology for Cardiopulmonary Diseases, Shanghai, China
| | - Linlin Zhang
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University Shanghai Medical College, Shanghai, China
| | - Bijun Zhu
- Shanghai Institute of Clinical Bioinformatics, Shanghai, China
- Shanghai Engineering Research for AI Technology for Cardiopulmonary Diseases, Shanghai, China
| | - Yifei Liu
- Center of Molecular Diagnosis and Therapy, The Second Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Liyang Li
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University Shanghai Medical College, Shanghai, China
| | - Jiayun Hou
- Shanghai Institute of Clinical Bioinformatics, Shanghai, China
| | - Mengjia Qian
- Shanghai Institute of Clinical Bioinformatics, Shanghai, China
| | - Nannan Zheng
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University Shanghai Medical College, Shanghai, China
| | - Yiming Zeng
- Center of Molecular Diagnosis and Therapy, The Second Hospital of Fujian Medical University, Quanzhou, Fujian Province, China.
| | - Chengshui Chen
- Quzhou Hospital of Wenzhou Medical University, Quzhou, Zhejiang Province, China.
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
| | - Xiangdong Wang
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University Shanghai Medical College, Shanghai, China.
- Shanghai Institute of Clinical Bioinformatics, Shanghai, China.
- Shanghai Engineering Research for AI Technology for Cardiopulmonary Diseases, Shanghai, China.
| |
Collapse
|
|
20
|
Chen J, Wang X, Schmalen A, Haines S, Wolff M, Ma H, Zhang H, Stoleriu MG, Nowak J, Nakayama M, Bueno M, Brands J, Mora AL, Lee JS, Krauss-Etschmann S, Dmitrieva A, Frankenberger M, Hofer TP, Noessner E, Moosmann A, Behr J, Milger K, Deeg CA, Staab-Weijnitz CA, Hauck SM, Adler H, Goldmann T, Gaede KI, Behrends J, Kammerl IE, Meiners S. Antiviral CD8 + T-cell immune responses are impaired by cigarette smoke and in COPD. Eur Respir J 2023; 62:2201374. [PMID: 37385655 PMCID: PMC10397470 DOI: 10.1183/13993003.01374-2022] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 05/24/2023] [Indexed: 07/01/2023]
Abstract
BACKGROUND Virus infections drive COPD exacerbations and progression. Antiviral immunity centres on the activation of virus-specific CD8+ T-cells by viral epitopes presented on major histocompatibility complex (MHC) class I molecules of infected cells. These epitopes are generated by the immunoproteasome, a specialised intracellular protein degradation machine, which is induced by antiviral cytokines in infected cells. METHODS We analysed the effects of cigarette smoke on cytokine- and virus-mediated induction of the immunoproteasome in vitro, ex vivo and in vivo using RNA and Western blot analyses. CD8+ T-cell activation was determined in co-culture assays with cigarette smoke-exposed influenza A virus (IAV)-infected cells. Mass-spectrometry-based analysis of MHC class I-bound peptides uncovered the effects of cigarette smoke on inflammatory antigen presentation in lung cells. IAV-specific CD8+ T-cell numbers were determined in patients' peripheral blood using tetramer technology. RESULTS Cigarette smoke impaired the induction of the immunoproteasome by cytokine signalling and viral infection in lung cells in vitro, ex vivo and in vivo. In addition, cigarette smoke altered the peptide repertoire of antigens presented on MHC class I molecules under inflammatory conditions. Importantly, MHC class I-mediated activation of IAV-specific CD8+ T-cells was dampened by cigarette smoke. COPD patients exhibited reduced numbers of circulating IAV-specific CD8+ T-cells compared to healthy controls and asthmatics. CONCLUSION Our data indicate that cigarette smoke interferes with MHC class I antigen generation and presentation and thereby contributes to impaired activation of CD8+ T-cells upon virus infection. This adds important mechanistic insight on how cigarette smoke mediates increased susceptibility of smokers and COPD patients to viral infections.
Collapse
Affiliation(s)
- Jie Chen
- Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
- Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China
- College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, China
- These authors contributed equally
| | - Xinyuan Wang
- Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
- Guangzhou Medical University, Guangzhou, China
- These authors contributed equally
| | - Adrian Schmalen
- Department of Veterinary Sciences, LMU Munich, Martinsried, Germany
- Metabolomics and Proteomics Core, Helmholtz Center Munich, Munich, Germany
| | - Sophia Haines
- Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Martin Wolff
- Institute of Experimental Medicine, Christian-Albrechts University Kiel, Kiel, Germany
| | - Huan Ma
- Institute of Experimental Medicine, Christian-Albrechts University Kiel, Kiel, Germany
| | - Huabin Zhang
- Neurosurgery Department, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mircea Gabriel Stoleriu
- Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
- Division of Thoracic Surgery Munich, University Clinic of Ludwig-Maximilians-University of Munich (LMU), Munich, Germany
- Asklepios Pulmonary Hospital, Gauting, Germany
| | - Johannes Nowak
- Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Misako Nakayama
- Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Marta Bueno
- Division of Pulmonary and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Judith Brands
- Division of Pulmonary and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ana L Mora
- Division of Pulmonary and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Davis Heart Lung Institute, Ohio State University, Columbus, OH, USA
| | - Janet S Lee
- Division of Pulmonary and Critical Care Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | | | - Anna Dmitrieva
- Institute of Asthma and Allergy Prevention, Helmholtz Center Munich, Member of the German Center of Lung Research (DZL), Munich, Germany
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Member of the German Center of Lung Research (DZL), Munich, Germany
| | - Marion Frankenberger
- Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Thomas P Hofer
- Immunoanalytics - Working Group Tissue Control of Immunocytes, Helmholtz Center Munich, Munich, Germany
| | - Elfriede Noessner
- Immunoanalytics - Working Group Tissue Control of Immunocytes, Helmholtz Center Munich, Munich, Germany
| | - Andreas Moosmann
- DZIF Group Host Control of Viral Latency and Reactivation, Department of Medicine III, LMU-Klinikum, Munich, Germany
- DZIF - German Center for Infection Research, Munich, Germany
| | - Jürgen Behr
- Department of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Katrin Milger
- Department of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Cornelia A Deeg
- Department of Veterinary Sciences, LMU Munich, Martinsried, Germany
| | - Claudia A Staab-Weijnitz
- Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Stefanie M Hauck
- Metabolomics and Proteomics Core, Helmholtz Center Munich, Munich, Germany
| | - Heiko Adler
- Institute of Asthma and Allergy Prevention, Helmholtz Center Munich, Member of the German Center of Lung Research (DZL), Munich, Germany
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Member of the German Center of Lung Research (DZL), Munich, Germany
| | - Torsten Goldmann
- Histology, Research Center Borstel, Leibniz Lung Center, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany
| | - Karoline I Gaede
- BioMaterialBank North, Research Center Borstel, Leibniz Lung Center, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Popgen 2.0 Network, (P2N), Borstel, Germany
| | - Jochen Behrends
- Core Facility Fluorescence Cytometry, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | - Ilona E Kammerl
- Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
- These authors contributed equally
| | - Silke Meiners
- Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
- Institute of Experimental Medicine, Christian-Albrechts University Kiel, Kiel, Germany
- Research Center Borstel, Leibniz Lung Center, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany
- These authors contributed equally
| |
Collapse
|
|
21
|
Zhang Q, Feng X, Hu W, Li C, Sun D, Peng Z, Wang S, Li H, Zhou M. Chronic obstructive pulmonary disease alters the genetic landscape and tumor immune microenvironment in lung cancer patients. Front Oncol 2023; 13:1169874. [PMID: 37388220 PMCID: PMC10301745 DOI: 10.3389/fonc.2023.1169874] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/23/2023] [Indexed: 07/01/2023] Open
Abstract
Background Chronic obstructive pulmonary disease (COPD) and lung cancer are leading causes of morbidity and mortality worldwide. Studies have reported molecular alterations in patients with lung cancer and in patients with COPD. However, few investigation has been conducted on the molecular characteristics of lung cancer patients with COPD. Materials and methods We performed a retrospective cohort study that included 435 patients with pathologically confirmed lung cancer at the Ruijin Hospital. For patients with documented spirometry, Global Initiative for Chronic Obstructive Lung Disease criteria were used to define COPD. For patients without documented spirometry, chest computed tomography and other clinical information were used to define COPD. Tumor tissue DNA was extracted from formalin-fixed paraffin-embedded samples. DNA mutation analysis, multiplex immunohistochemistry (mIHC), calculation of tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH), and predication of neoantigens were performed. Results Although SNV mutations in lung cancer patients with COPD (G1 group) were generally higher than those in lung cancer patients without COPD (G2 group), the difference in the number of mutations was insignificant between the two groups. Of the 35 mutated genes, the number of them was higher in G1 than in G2, except that of EGFR. PI3K-Akt signaling pathway was enriched from significantly different genes. While TMB and MATH levels were not significantly different, the tumor neoantigen burdenwas markedly higher in G1 than that in G2. The level of CD68+ macrophages was significant higher in the stroma and total areas in the G1 group than in G2 group. The level of CD8+ lymphocytes was markedly higher in the stroma and showed a clear tendency forhigher expression in the G1 group than inthe G2 group. No significant differences were observed for the level of programmed death-ligand 1+ (PD-L1+), programmed death 1+ (PD-1+), and CD68PD-L1 in the stroma, tumor and total areas. Conclusion Our study revealed different genetic aberrations and pathways, higher neoantigen burden, and higher level of CD68+ macrophages and CD8+ T lymphocytes in lung cancer patients with COPD. Our investigation implies that the existence of COPD should be considered and immunotherapy is a potential choice when treating lung cancer patients with COPD.
Collapse
Affiliation(s)
- Qiurui Zhang
- Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, China
| | - Xijia Feng
- Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiting Hu
- Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, China
| | - Chengqiang Li
- Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Debin Sun
- Genecast Biotechnology Co., Ltd., Wuxi, Jiangsu, China
| | - Zhao Peng
- Genecast Biotechnology Co., Ltd., Wuxi, Jiangsu, China
| | | | - Hecheng Li
- Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Zhou
- Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, China
| |
Collapse
|
|
22
|
Yi M, Li T, Niu M, Wu Y, Zhao Z, Wu K. TGF-β: A novel predictor and target for anti-PD-1/PD-L1 therapy. Front Immunol 2022; 13:1061394. [PMID: 36601124 PMCID: PMC9807229 DOI: 10.3389/fimmu.2022.1061394] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Transforming growth factor-β (TGF-β) signaling regulates multiple physiological processes, such as cell proliferation, differentiation, immune homeostasis, and wound healing. Besides, TGF-β plays a vital role in diseases, including cancer. Accumulating evidence indicates that TGF-β controls the composition and behavior of immune components in the tumor microenvironment (TME). Advanced cancers leverage TGF-β to reshape the TME and escape immune surveillance. TGF-β-mediated immune evasion is an unfavorable factor for cancer immunotherapy, especially immune checkpoint inhibitors (ICI). Numerous preclinical and clinical studies have demonstrated that hyperactive TGF-β signaling is closely associated with ICI resistance. It has been validated that TGF-β blockade synergizes with ICI and overcomes treatment resistance. TGF-β-targeted therapies, including trap and bispecific antibodies, have shown immense potential for cancer immunotherapy. In this review, we summarized the predictive value of TGF-β signaling and the prospects of TGF-β-targeted therapies for cancer immunotherapy.
Collapse
Affiliation(s)
- Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Tianye Li
- Department of Gynecology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuze Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenyu Zhao
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,*Correspondence: Kongming Wu, ; Zhenyu Zhao,
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,*Correspondence: Kongming Wu, ; Zhenyu Zhao,
| |
Collapse
|
|
23
|
Zeng Z, Qu J, Yao Y, Xu F, Lu S, Zhang P, Yao Y, Li N, Zhou J, Wang Y. Clinical outcomes and risk factor of immune checkpoint inhibitors-related pneumonitis in non-small cell lung cancer patients with chronic obstructive pulmonary disease. BMC Pulm Med 2022; 22:458. [PMID: 36456932 PMCID: PMC9716670 DOI: 10.1186/s12890-022-02190-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 10/10/2022] [Indexed: 12/03/2022] Open
Abstract
OBJECTIVES Chronic obstructive pulmonary disease (COPD) is the most common co-morbidity associated with non-small cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors related pneumonitis (CIP) is a common immune-related adverse event that can be life-threatening. The study aims to evaluate the association of COPD with the incidence and outcome of CIP in NSCLC patients receiving immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS We retrospectively collected data from 122 patients diagnosed with NSCLC and treated with ICIs in our department. Baseline pulmonary function was performed in the whole cohort. The incidence, risk factors, treatment and outcome of CIP patients were evaluated. Furthermore, the efficacy of ICIs in patients with COPD was analyzed. RESULTS Nineteen patients (15.5%, 19/122) developed CIP during ICIs treatment, most patients with CIP were grade 1-2, and the incidence of CIP was comparable in patients with COPD and those without COPD (18.0% vs. 13.1%, P = 0.618). In addition, an increasing trend in the incidence of CIP among patients with pulmonary fibrosis on baseline chest CT scans (27.3% vs. 13.0%, P = 0.093). There is a longer progression-free survival in COPD patients than the non-COPD patients. CONCLUSION Coexisting COPD did not predict the higher risk of CIP in NSCLC treated with ICIs therapy. Nevertheless, pre-existing pulmonary fibrosis on CT scan may increase the risk of CIP, close monitoring is advised in these patients during ICIs.
Collapse
Affiliation(s)
- Zhu Zeng
- grid.13402.340000 0004 1759 700XDepartment of Respiratory Diseases, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
| | - Jingjing Qu
- grid.13402.340000 0004 1759 700XDepartment of Respiratory Diseases, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
| | - Yake Yao
- grid.13402.340000 0004 1759 700XDepartment of Respiratory Diseases, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
| | - Fei Xu
- grid.13402.340000 0004 1759 700XDepartment of Respiratory Diseases, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
| | - Shan Lu
- grid.13402.340000 0004 1759 700XDepartment of Respiratory Diseases, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
| | - Pei Zhang
- grid.13402.340000 0004 1759 700XDepartment of Respiratory Diseases, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
| | - Yinan Yao
- grid.13402.340000 0004 1759 700XDepartment of Respiratory Diseases, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
| | - Ning Li
- grid.13402.340000 0004 1759 700XDepartment of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianying Zhou
- grid.13402.340000 0004 1759 700XDepartment of Respiratory Diseases, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China ,grid.13402.340000 0004 1759 700XDepartment of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Qingchun Road 79, Hangzhou, China
| | - Yuehong Wang
- grid.13402.340000 0004 1759 700XDepartment of Respiratory Diseases, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China ,grid.13402.340000 0004 1759 700XDepartment of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Qingchun Road 79, Hangzhou, China
| |
Collapse
|
|
24
|
Lin M, Huang Z, Chen Y, Xiao H, Wang T. Lung cancer patients with chronic obstructive pulmonary disease benefit from anti-PD-1/PD-L1 therapy. Front Immunol 2022; 13:1038715. [PMID: 36532019 PMCID: PMC9751394 DOI: 10.3389/fimmu.2022.1038715] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/17/2022] [Indexed: 12/04/2022] Open
Abstract
Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are two of the most fatal respiratory diseases, seriously threatening human health and imposing a heavy burden on families and society. Although COPD is a significant independent risk factor for LC, it is still unclear how COPD affects the prognosis of LC patients, especially when LC patients with COPD receive immunotherapy. With the development of immune checkpoint inhibition (ICI) therapy, an increasing number of inhibitors of programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) have been applied to the treatment of LC. Recent studies suggest that LC patients with COPD may benefit more from immunotherapy. In this review, we systematically summarized the outcomes of LC patients with COPD after anti-PD-1/PD-L1 treatment and discussed the tumor immune microenvironment (TIME) regulated by COPD in LC immunotherapy, which provides novel insights for the clinical treatment of LC patients with COPD.
Collapse
Affiliation(s)
- Mao Lin
- Department of Pharmacy, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Zongyao Huang
- Department of Pathology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yingfu Chen
- Department of Pharmacy, Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
| | - Hongtao Xiao
- Department of Pharmacy, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Ting Wang
- Department of Clinical Research, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China,*Correspondence: Ting Wang,
| |
Collapse
|
|
25
|
Zhang K, Zhou C, Gao J, Yu P, Lin X, Xie X, Liu M, Zhang J, Xie Z, Cui F, Li S, Passiglia F, Stella GM, Qin Y. Treatment response and safety of immunotherapy for advanced non-small cell lung cancer with comorbid chronic obstructive pulmonary disease: a retrospective cohort study. Transl Lung Cancer Res 2022; 11:2306-2317. [PMID: 36519030 PMCID: PMC9742614 DOI: 10.21037/tlcr-22-667] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 11/03/2022] [Indexed: 06/07/2024]
Abstract
BACKGROUND Immunotherapy has provided a novel therapeutic option for lung cancer but studies involving patients with advanced non-small cell lung cancer (NSCLC) coupled with various degrees of comorbid chronic obstructive pulmonary disease (COPD) are limited. Thus, we performed a retrospective cohort study to optimize the use of immunotherapy in this special population. METHODS We enrolled a total of 99 patients with advanced (stage IIIB/C-IV) NSCLC with comorbid COPD who had received immune checkpoint inhibitors (ICIs) according to the inclusion and exclusion criteria. They were divided into four groups according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline criteria as follows: no COPD group (n1=19), mild COPD group (n2=24), moderate COPD group (n3=31), and severe COPD group (n4=25). Routine blood, imaging characteristics, related cytokines including interleukin (IL)-6, IL-8, IL-10, etc., Krebs Von den Lungen (KL)-6, and corresponding indicators of immune-related adverse events (irAEs), incidence of irAEs, objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were recorded and analyzed. Comparability of baseline factors above and clinical characteristics were evaluated. RESULTS There were statistically significant differences in the incidence of irAEs among the four groups (P=0.003). The incidence of irAEs in patients with no COPD (n1, 21.1%) and mild to moderate COPD (n2/3, 8.3%, 32.3%) was lower than that in patients with severe COPD (n4, 56.0%) (P=0.003). The median PFS of the mild to moderate COPD group was significantly longer than the severe COPD group (19.0 vs. 8.00 months, log-rank P=0.004). A significant increase of both ORR (P=0.004) and DCR (P=0.037), as well as higher IL-6 (P=0.000), IL-8 (P=0.026), and IL-10 (P=0.010) levels, have been observed in the mild to moderate COPD group compared with severe COPD group. IL-6 level was an independent factor influencing PFS [P=0.007, 95% confidence interval (95% CI): 1.000-1.002] and COPD grading was an independent predictor of irAEs (P=0.037, 95% CI: 1.035-3.039). CONCLUSIONS Immunotherapy should be selected with caution for advanced NSCLC patients with comorbid severe COPD, considering the limited efficacy and the increased risk of immune-related adverse events related to the immune-checkpoint inhibitors administration in this special population.
Collapse
Affiliation(s)
- Kening Zhang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Chengzhi Zhou
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiabo Gao
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Pei Yu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xinqing Lin
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaohong Xie
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ming Liu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiexia Zhang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhanhong Xie
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Fei Cui
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shiyue Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Francesco Passiglia
- Department of Oncology, S. Luigi Gonzaga Hospital, University of Turin, Orbassano (TO), Italy
| | - Giulia Maria Stella
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy
- Department of Medical Sciences and Infective Diseases, Unit of Respiratory Diseases, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
| | - Yinyin Qin
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
26
|
Qi C, Sun SW, Xiong XZ. From COPD to Lung Cancer: Mechanisms Linking, Diagnosis, Treatment, and Prognosis. Int J Chron Obstruct Pulmon Dis 2022; 17:2603-2621. [PMID: 36274992 PMCID: PMC9586171 DOI: 10.2147/copd.s380732] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/30/2022] [Indexed: 11/23/2022] Open
Abstract
Many studies have proved that the pathogenesis of the chronic obstructive pulmonary disease (COPD) and lung cancer is related, and may cause and affect each other to a certain extent. In fact, the change of chronic airway obstruction will continue to have an impact on the screening, treatment, and prognosis of lung cancer.In this comprehensive review, we outlined the links and heterogeneity between COPD and lung cancer and finds that factors such as gene expression and genetic susceptibility, epigenetics, smoking, epithelial mesenchymal transformation (EMT), chronic inflammation, and oxidative stress injury may all play a role in the process. Although the relationship between these two diseases have been largely determined, the methods to prevent lung cancer in COPD patients are still limited. Early diagnosis is still the key to a better prognosis. Thus, it is necessary to establish more intuitive screening evaluation criteria and find suitable biomarkers for lung cancer screening in high-risk populations with COPD. Some studies have indicated that COPD may change the efficacy of anti-tumor therapy by affecting the response of lung cancer patients to immune checkpoint inhibitors (ICIs). And for lung cancer patients with COPD, the standardized management of COPD can improve the prognosis. The treatment of lung cancer patients with COPD is an individualized, comprehensive, and precise process. The development of new targets and new strategies of molecular targeted therapy may be the breakthrough for disease treatment in the future.
Collapse
Affiliation(s)
- Chang Qi
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Sheng-Wen Sun
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Xian-Zhi Xiong
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China,Correspondence: Xian-Zhi Xiong, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People’s Republic of China, Tel/Fax +86 27-85726705, Email
| |
Collapse
|
|
27
|
Uliński R, Kwiecień I, Domagała-Kulawik J. Lung Cancer in the Course of COPD-Emerging Problems Today. Cancers (Basel) 2022; 14:cancers14153819. [PMID: 35954482 PMCID: PMC9367492 DOI: 10.3390/cancers14153819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/26/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022] Open
Abstract
Tobacco smoking remains the main cause of tobacco-dependent diseases like lung cancer, chronic obstructive pulmonary disease (COPD), in addition to cardiovascular diseases and other cancers. Whilst the majority of smokers will not develop either COPD or lung cancer, they are closely related diseases, occurring as co-morbidities at a higher rate than if they were independently triggered by smoking. A patient with COPD has a four- to six-fold greater risk of developing lung cancer independent of smoking exposure, when compared to matched smokers with normal lung function. The 10 year risk is about 8.8% in the COPD group and only 2% in patients with normal lung function. COPD is not a uniform disorder: there are different phenotypes. One of them is manifested by the prevalence of emphysema and this is complicated by malignant processes most often. Here, we present and discuss the clinical problems of COPD in patients with lung cancer and against lung cancer in the course of COPD. There are common pathological pathways in both diseases. These are inflammation with participation of macrophages and neutrophils and proteases. It is known that anticancer immune regulation is distorted towards immunosuppression, while in COPD the elements of autoimmunity are described. Cytotoxic T cells, lymphocytes B and regulatory T cells with the important role of check point molecules are involved in both processes. A growing number of lung cancer patients are treated with immune check point inhibitors (ICIs), and it was found that COPD patients may have benefits from this treatment. Altogether, the data point to the necessity for deeper analysis and intensive research studies to limit the burden of these serious diseases by prevention and by elaboration of specific therapeutic options.
Collapse
Affiliation(s)
- Robert Uliński
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Iwona Kwiecień
- Laboratory of Hematology and Flow Cytometry, Department of Internal Medicine and Hematology, Military Institute of Medicine, 04-141 Warsaw, Poland
| | - Joanna Domagała-Kulawik
- Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, 02-097 Warsaw, Poland
- Correspondence:
| |
Collapse
|
|
28
|
Ma H, Zhang Q, Zhao Y, Zhang Y, Zhang J, Chen G, Tan Y, Zhang Q, Duan Q, Sun T, Qi C, Li F. Molecular and Clinicopathological Characteristics of Lung Cancer Concomitant Chronic Obstructive Pulmonary Disease (COPD). Int J Chron Obstruct Pulmon Dis 2022; 17:1601-1612. [PMID: 35860812 PMCID: PMC9293488 DOI: 10.2147/copd.s363482] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/25/2022] [Indexed: 11/23/2022] Open
Abstract
Introduction Chronic obstructive pulmonary disease (COPD) and lung cancer often coexist, but its pathophysiology and genomics features are still unclear. Methods In this study, we retrospectively collected lung cancer concomitant COPD (COPD-LC) and non-COPD lung cancer (non-COPD-LC) patients, who performed next generation sequencing (NGS) and had clinicopathological information simultaneously. The COPD-LC data from the TCGA cohort were collected to conduct further analysis. Results A total of 51 COPD-LC patients and 88 non-COPD-LC patients were included in the study. Clinicopathological analysis showed that proportion of male gender, older age, and smoking patients were all substantially higher in COPD-LC group than in non-COPD-LC group (all P<0.01). Comparing the genomic data of the two groups in our cohort, COPD-LC had higher mutation frequency of LRP1B (43% vs 9%, P = 0.001), EPHA5 (24% vs 1%, P = 0.002), PRKDC (14% vs 1%, P = 0.039), PREX2 (14% vs 0%, P = 0.012), and FAT1 (14% vs 0%, P = 0.012), which had a relationship with improved tumor immunity. Immunotherapy biomarker of PD-L1 positive expression (62.5% vs 52.0%, P = 0.397) and tumor mutation burden (TMB, median TMB: 7.09 vs 2.94, P = 0.004) also were higher in COPD-LC. In addition, RNA data from TCGA further indicated tumor immunity increased in COPD-LC. Whereas, COPD-LC had lower frequency of EGFR mutation (19% vs 50%, P = 0.013) and EGFR mutant COPD-LC treated with EGFR-TKI had worse progression-free survival (PFS) (HR = 3.52, 95% CI: 1.27–9.80, P = 0.01). Conclusion In this retrospective study, we first explored molecular features of COPD-LC in a Chinese population. Although COPD-LC had lower EGFR mutant frequency and worse PFS with target treatment, high PD-L1 expression and TMB indicated these patients may benefit from immunotherapy.
Collapse
Affiliation(s)
- Hongxia Ma
- Pneumology Department, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, The Xinjiang Uygur Autonomous Region, People's Republic of China
| | - Qian Zhang
- Pneumology Department, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, The Xinjiang Uygur Autonomous Region, People's Republic of China
| | - Yanwen Zhao
- Pneumology Department, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, The Xinjiang Uygur Autonomous Region, People's Republic of China
| | - Yaohui Zhang
- Pneumology Department, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, The Xinjiang Uygur Autonomous Region, People's Republic of China
| | - Jingjing Zhang
- Pneumology Department, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, The Xinjiang Uygur Autonomous Region, People's Republic of China
| | - Guoqing Chen
- Pneumology Department, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, The Xinjiang Uygur Autonomous Region, People's Republic of China
| | - Yuan Tan
- The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China.,Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China.,The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China
| | - Qin Zhang
- The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China.,Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China.,The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China
| | - Qianqian Duan
- The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China.,Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China.,The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China
| | - Tingting Sun
- The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China.,Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China.,The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China
| | - Chuang Qi
- The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China.,Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China.,The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, Jiangsu Province, People's Republic of China
| | - Fengsen Li
- Pneumology Department, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, The Xinjiang Uygur Autonomous Region, People's Republic of China
| |
Collapse
|
|
29
|
Noda Y, Shiroyama T, Masuhiro K, Amiya S, Enomoto T, Adachi Y, Hara R, Niitsu T, Naito Y, Miyake K, Koyama S, Hirata H, Nagatomo I, Takeda Y, Kumanogoh A. Quantitative evaluation of emphysema for predicting immunotherapy response in patients with advanced non-small-cell lung cancer. Sci Rep 2022; 12:8881. [PMID: 35614345 PMCID: PMC9133115 DOI: 10.1038/s41598-022-13131-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 05/17/2022] [Indexed: 11/26/2022] Open
Abstract
The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small-cell lung cancer (NSCLC) might depend on the presence of emphysema, but this association is not established. We aimed to investigate if quantitively and automatically measuring emphysema can predict the effect of ICIs. We retrospectively analyzed 56 patients with NSCLC who underwent immunotherapy at our hospital. We used the Goddard scoring system (GS) to evaluate the severity of emphysema on baseline CT scans using three-dimensional image analysis software. The emphysema group (GS ≥ 1) showed better progression-free survival (PFS) than the non-emphysema group (GS = 0) (6.5 vs. 2.3 months, respectively, p < 0.01). Multivariate analyses revealed that good performance status, GS of ≥ 1, and high expression of PD-L1 were independently associated with better PFS, while smoking status was not. In conclusion, quantitative evaluation of emphysema can be an objective parameter for predicting the therapeutic effects of ICIs in patients with NSCLC. Our findings can be used to generate hypotheses for future studies.
Collapse
Affiliation(s)
- Yoshimi Noda
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Takayuki Shiroyama
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan.
| | - Kentaro Masuhiro
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Saori Amiya
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Takatoshi Enomoto
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Yuichi Adachi
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Reina Hara
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Takayuki Niitsu
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Yujiro Naito
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Kotaro Miyake
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Shohei Koyama
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Haruhiko Hirata
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Izumi Nagatomo
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Yoshito Takeda
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Atsushi Kumanogoh
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan.,Department of Immunopathology, WPI, Immunology Frontier Research Center (iFReC), Osaka University, Suita, Osaka, Japan.,Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka, Japan.,Center for Infectious Diseases for Education and Research (CiDER), Osaka University, Suita, Osaka, Japan
| |
Collapse
|
|
30
|
Feng Z, Yin Y, Liu B, Wang L, Chen M, Zhu Y, Zhang H, Sun D, Qin J. ZNF143 Expression is Associated with COPD and Tumor Microenvironment in Non-Small Cell Lung Cancer. Int J Chron Obstruct Pulmon Dis 2022; 17:685-700. [PMID: 35400998 PMCID: PMC8986213 DOI: 10.2147/copd.s352392] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/24/2022] [Indexed: 11/23/2022] Open
Abstract
Background Chronic obstructive pulmonary disease (COPD) is an inflammatory-related disease highly associated with increased lung cancer risk. Studies have explored the tumor promoting roles for zinc finger protein 143 (ZNF143). However, the role of ZNF143 in COPD and tumor microenvironment of non-small cell lung cancer (NSCLC) has not been fully elucidated. Methods COPD-related key genes were identified by differential gene expression evaluation, WGCNA and SVM-RFE analysis using mRNA expression data retrieved from public databases. ROC analysis was conducted to evaluate the diagnostic value of ZNF143. Correlation between ZNF143 and clinic-pathological features, associations with tumor-infiltrating immune cells (TICs) and the relationship with predictors of immunotherapy efficacy were explored. ZNF143 gene expression was validated by qRT-PCR using an independent cohort. Results Bioinformatic and machine learning analysis showed that ZNF143 was a COPD-related gene. ZNF143 expression was significantly upregulated in COPD and is a potential diagnostic biomarker in COPD with AUC > 0.85. ZNF143 expression was significantly upregulated in lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). ZNF143 expression levels were significantly higher in LUAD patients with COPD relative to the levels in patients only with LUAD. Upregulation of ZNF143 in patients with comorbidity of NSCLC and COPD was further confirmed by qRT-PCR analysis. High expression of ZNF143 was significantly correlated with advanced TNM stage in LUSC. High ZNF143 expression was associated with activated TICs in both LUAD and LUSC samples. Moreover, ZNF143 expression was significantly correlated with the levels of several known predictors of immunotherapy efficacy, including PD-L1, PD-L2, TMB and TIDE in NSCLC. Conclusion ZNF143 is a novel COPD biomarker. High expression level of ZNF143 is associated with immune microenvironment and high risk of progression of COPD to NSCLC.
Collapse
Affiliation(s)
- Zhenxing Feng
- Department of Radiology, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Yan Yin
- Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Bin Liu
- Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Lei Wang
- Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Miaomiao Chen
- Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Yue Zhu
- Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Hong Zhang
- Department of Radiology, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Daqiang Sun
- Department of Thoracic Surgery, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
- Daqiang Sun, Department of Thoracic Surgery, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China, Email
| | - Jianwen Qin
- Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
- Correspondence: Jianwen Qin, Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China, Email
| |
Collapse
|
|
31
|
Shen YL, Shen CI, Chiang CL, Huang HC, Chou KT, Chiu CH, Chen YM, Luo YH. Reduced FEV1 as Prognostic Factors in Patients With Advanced NSCLC Receiving Immune Checkpoint Inhibitors. Front Med (Lausanne) 2022; 9:860733. [PMID: 35391883 PMCID: PMC8980716 DOI: 10.3389/fmed.2022.860733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 02/28/2022] [Indexed: 12/03/2022] Open
Abstract
Background The aim of study is to investigate the influence of pulmonary function on the prognosis in patients with advanced non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICI). Patients and Methods Data were collected retrospectively from 151 patients with stage IV NSCLC who received ICI and completed spirometry before ICI therapy in Taipei Veterans General Hospital between January 2016 and December 2020. The co-primary end points were overall survival (OS) and progression-free survival (PFS) between groups divided by 80% predicted FEV1 since ICI therapy started; the secondary outcomes were objective response rate. Results Among 151 patients enrolled to this study, 67.5% of patients were men, 75.5% were adenocarcinoma, 24.5% had known targetable driver mutation, 33.8% received first-line ICI, and 62.8% received ICI monotherapy. The objective response rate was 24.5% and disease control rate was 54.3%. In multivariable analysis, patient with reduced FEV1 had inferior PFS (FEV1 < 80% vs. FEV1 ≥ 80%, adjusted HR = 1.80, P = 0.006) and OS (FEV1 < 80% vs. FEV1 ≥ 80%, adjusted HR = 2.50, P < 0.001). Median PFS and OS in the preserved FEV1 group (≥80% predicted FEV1) compared to the reduced FEV1 group (<80% predicted FEV1) were 5.4 vs. 2.9 months (HR = 1.76, P = 0.003) and 34.9 vs. 11.1 months (HR = 2.44, P < 0.001), respectively. The other independent prognostic factors of OS include stage IVA disease (adjusted HR = 0.57, P = 0.037), initial liver metastasis (adjusted HR = 2.00, P = 0.049), ICI monotherapy (adjusted HR = 1.73, P = 0.042) and ICI related pneumonitis (adjusted HR = 3 .44, P = 0.025). Conclusions Reduced FEV1 is strongly associated with inferior clinical outcomes in patients with advanced NSCLC treated with ICI.
Collapse
Affiliation(s)
- Yi-Luen Shen
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Chest Medicine, Department of Internal Medicine, Asia University Hospital, Taichung, Taiwan
| | - Chia-I Shen
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chi-Lu Chiang
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsu-Ching Huang
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Kun-Ta Chou
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chao-Hua Chiu
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yuh-Min Chen
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yung-Hung Luo
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- *Correspondence: Yung-Hung Luo
| |
Collapse
|
|
32
|
Evaluation of Microscopic Tumour Extension in Localized Stage Non-Small-Cell Lung Cancer for Stereotactic Radiotherapy Planning. Cancers (Basel) 2022; 14:cancers14051282. [PMID: 35267589 PMCID: PMC8909894 DOI: 10.3390/cancers14051282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/22/2022] [Accepted: 03/01/2022] [Indexed: 02/04/2023] Open
Abstract
Background: Stereotactic radiotherapy for localised stage non-small-cell lung carcinoma (NSCLC) is an alternative indication for patients who are inoperable or refuse surgery. A study showed that the microscopic tumour extension (ME) of NSCLC varied according to the histological type, which allowed us to deduce adapted margins for the clinical target volume (CTV). However, to date, no study has been able to define the most relevant margins for patients with stage 1 tumours. Methods: We performed a retrospective analysis including patients with adenocarcinoma (ADC) or squamous cell carcinoma (SCC) of localised stage T1N0 or T2aN0 who underwent surgery. The ME was measured from this boundary. The profile of the type of tumour spread was also evaluated. Results: The margin required to cover the ME of a localised NSCLC with a 95% probability is 4.4 mm and 2.9 mm for SCC and ADC, respectively. A significant difference in the maximum distance of the ME between the tumour-infiltrating lymphocytes (TILs), 0−10% and 50−90% (p < 0.05), was noted for SCC. There was a significant difference in the maximum ME distance based on whether the patient had chronic obstructive pulmonary disease (COPD) (p = 0.011) for ADC. Multivariate analysis showed a statistically significant relationship between the maximum microextension distance and size with the shrinkage coefficient. Conclusion: This study definitively demonstrated that the ME depends on the pathology subtype of NSCLC. According to International Commission on Radiation Units and Measurements (ICRU) reports, 50, 62 and 83 CTV margins, proposed by these results, should be added to the GTV (Gross tumour volume). When stereotactic body radiation therapy is used, this approach should be considered in conjunction with the dataset and other margins to be applied.
Collapse
|
|
33
|
PERROTTA F, D’AGNANO V, SCIALÒ F, KOMICI K, ALLOCCA V, NUCERA F, SALVI R, STELLA GM, BIANCO A. Evolving concepts in COPD and lung cancer: a narrative review. Minerva Med 2022; 113:436-448. [DOI: 10.23736/s0026-4806.22.07962-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
|
|
34
|
Skurikhin E, Pershina O, Zhukova M, Widera D, Ermakova N, Pan E, Pakhomova A, Morozov S, Kubatiev A, Dygai A. Potential of Stem Cells and CART as a Potential Polytherapy for Small Cell Lung Cancer. Front Cell Dev Biol 2021; 9:778020. [PMID: 34926461 PMCID: PMC8678572 DOI: 10.3389/fcell.2021.778020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/18/2021] [Indexed: 12/15/2022] Open
Abstract
Despite the increasing urgency of the problem of treating small cell lung cancer (SCLC), information on the causes of its development is fragmentary. There is no complete understanding of the features of antitumor immunity and the role of the microenvironment in the development of SCLC resistance. This impedes the development of new methods for the diagnosis and treatment of SCLC. Lung cancer and chronic obstructive pulmonary disease (COPD) have common pathogenetic factors. COPD is a risk factor for lung cancer including SCLC. Therefore, the search for effective approaches to prevention, diagnosis, and treatment of SCLC in patients with COPD is an urgent task. This review provides information on the etiology and pathogenesis of SCLC, analyses the effectiveness of current treatment options, and critically evaluates the potential of chimeric antigen receptor T cells therapy (CART therapy) in SCLC. Moreover, we discuss potential links between lung cancer and COPD and the role of endothelium in the development of COPD. Finally, we propose a new approach for increasing the efficacy of CART therapy in SCLC.
Collapse
Affiliation(s)
- Evgenii Skurikhin
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Olga Pershina
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Mariia Zhukova
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Darius Widera
- Stem Cell Biology and Regenerative Medicine Group, School of Pharmacy, University of Reading, Reading, United Kingdom
| | - Natalia Ermakova
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Edgar Pan
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Angelina Pakhomova
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Sergey Morozov
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Aslan Kubatiev
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Alexander Dygai
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| |
Collapse
|
|
35
|
Nair VS, Eaton K, McGarry Houghton A. A case series of morbid COPD exacerbations during immune checkpoint inhibitor therapy in cancer patients. Respir Med Case Rep 2021; 34:101541. [PMID: 34760616 PMCID: PMC8566897 DOI: 10.1016/j.rmcr.2021.101541] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 11/09/2022] Open
Abstract
Background Immune checkpoint inhibitor therapy is rapidly becoming front line adjuvant or primary therapy in a number of solid cancer types. Since many of these cancers are a result of tobacco smoking, a large number of these patients will have underlying comorbid conditions attributed to smoking such as Chronic Obstructive Pulmonary Disease (COPD). The effect of immune checkpoint inhibitor therapy on COPD is not well documented, and COPD exacerbations are not currently considered a pulmonary associated immune checkpoint inhibitor toxicity in current guidelines. Case presentation We describe and summarize here a series of patients with prolonged and severe COPD exacerbations upon the initiation of immune checkpoint inhibitor therapy for cancers of the skin and lung without radiographic evidence of pneumonitis. Conclusions COPD exacerbation from immune checkpoint inhibitor is not reported in the literature and is associated with prolonged and severe episodes without radiographic evidence of pneumonitis. Awareness of this potential morbid toxicity and research efforts to understand its etiology are required.
Collapse
Affiliation(s)
- Viswam S Nair
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave, Seattle, WA, 98109, USA.,Division of Pulmonary, Critical Care & Sleep Medicine, University of Washington School of Medicine, 1959 NE Pacific St, Seattle, WA, 98195, USA
| | - Keith Eaton
- Thoracic, Head & Neck Medical Oncology, Seattle Cancer Care Alliance, 1354 Aloha St, Seattle, WA, 98109, USA.,Division of Medical Oncology, University of Washington School of Medicine, 1959 NE Pacific St, Seattle, WA, 98195, USA
| | - A McGarry Houghton
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave, Seattle, WA, 98109, USA.,Division of Pulmonary, Critical Care & Sleep Medicine, University of Washington School of Medicine, 1959 NE Pacific St, Seattle, WA, 98195, USA
| |
Collapse
|
|
36
|
Takayama Y, Nakamura T, Fukushiro Y, Mishima S, Masuda K, Shoda H. Coexistence of Emphysema With Non-small-cell Lung Cancer Predicts the Therapeutic Efficacy of Immune Checkpoint Inhibitors. In Vivo 2021; 35:467-474. [PMID: 33402498 DOI: 10.21873/invivo.12280] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND/AIM Chronic obstructive pulmonary disease coexisting with non-small-cell lung cancer (NSCLC) was reported to be associated with a longer progression-free survival (PFS) in patients treated with immune checkpoint inhibitors (ICIs). In the present study, we investigated the impact of emphysematous change on the treatment response to ICIs in patients with NSCLC. PATIENTS AND METHODS A total of 153 patients with advanced NSCLC who received ICIs (nivolumab, pembrolizumab, or atezolizumab) at our hospital from January 2016 to May 2019 were retrospectively enrolled. RESULTS According to the Goddard scoring system, 71 (46.4%) patients were classified as having emphysema and 82 (53.6%) as having no emphysema. Multivariate analysis showed that a good performance status and coexisting emphysema (hazard ratio=0.49; 95% confidence intervaI=0.28-0.84; p=0.010) were independent predictors of a better PFS. CONCLUSION Recognizing emphysema coexisting with NSCLC may help predict the therapeutic efficacy of ICIs in such patients.
Collapse
Affiliation(s)
- Yusuke Takayama
- Department of Respiratory Medicine, Hiroshima Citizens Hospital, Hiroshima, Japan;
| | - Takashi Nakamura
- Department of Respiratory Medicine, Hiroshima General Hospital, Hatsukaichi, Japan
| | - Yuki Fukushiro
- Department of Respiratory Medicine, Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Shohei Mishima
- Department of Respiratory Medicine, Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Ken Masuda
- Department of Respiratory Medicine, Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Hiroyasu Shoda
- Department of Respiratory Medicine, Hiroshima Citizens Hospital, Hiroshima, Japan
| |
Collapse
|
|
37
|
Nakano-Narusawa Y, Yokohira M, Yamakawa K, Ye J, Tanimoto M, Wu L, Mukai Y, Imaida K, Matsuda Y. Relationship between Lung Carcinogenesis and Chronic Inflammation in Rodents. Cancers (Basel) 2021; 13:cancers13122910. [PMID: 34200786 PMCID: PMC8230400 DOI: 10.3390/cancers13122910] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 06/01/2021] [Accepted: 06/08/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Lung cancer is the most common cause of cancer-related deaths worldwide. There are various risk factors for lung cancer, including tobacco smoking, inhalation of dust particles, chronic inflammation, and genetic factors. Chronic inflammation has been considered a key factor that promotes tumor progression via production of cytokines, chemokines, cytotoxic mediators, and reactive oxygen species by inflammatory cells. Here, we review rodent models of lung tumor induced by tobacco, tobacco-related products, and pro-inflammatory materials as well as genetic modifications, and discuss the relationship between chronic inflammation and lung tumor. Through this review, we hope to clarify the effects of chronic inflammation on lung carcinogenesis and help develop new treatments for lung cancer. Abstract Lung cancer remains the leading cause of cancer-related deaths, with an estimated 1.76 million deaths reported in 2018. Numerous studies have focused on the prevention and treatment of lung cancer using rodent models. Various chemicals, including tobacco-derived agents induce lung cancer and pre-cancerous lesions in rodents. In recent years, transgenic engineered rodents, in particular, those generated with a focus on the well-known gene mutations in human lung cancer (KRAS, EGFR, and p53 mutations) have been widely studied. Animal studies have revealed that chronic inflammation significantly enhances lung carcinogenesis, and inhibition of inflammation suppresses cancer progression. Moreover, the reduction in tumor size by suppression of inflammation in animal experiments suggests that chronic inflammation influences the promotion of tumorigenesis. Here, we review rodent lung tumor models induced by various chemical carcinogens, including tobacco-related carcinogens, and transgenics, and discuss the roles of chronic inflammation in lung carcinogenesis.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Yoko Matsuda
- Correspondence: ; Tel.: +81-87-891-2109; Fax: +81-87-891-2112
| |
Collapse
|
|
38
|
Narayanapillai SC, Han YH, Song JM, Kebede ME, Upadhyaya P, Kassie F. Modulation of the PD-1/PD-L1 immune checkpoint axis during inflammation-associated lung tumorigenesis. Carcinogenesis 2021; 41:1518-1528. [PMID: 32602900 DOI: 10.1093/carcin/bgaa059] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 05/28/2020] [Indexed: 12/27/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a significant risk factor for lung cancer. One potential mechanism through which COPD contributes to lung cancer development could be through generation of an immunosuppressive microenvironment that allows tumor formation and progression. In this study, we compared the status of immune cells and immune checkpoint proteins in lung tumors induced by the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) or NNK + lipopolysaccharide (LPS), a model for COPD-associated lung tumors. Compared with NNK-induced lung tumors, NNK+LPS-induced lung tumors exhibited an immunosuppressive microenvironment characterized by higher relative abundances of PD-1+ tumor-associated macrophages, PD-L1+ tumor cells, PD-1+ CD4 and CD8 T lymphocytes and FOXP3+ CD4 and CD8 T lymphocytes. Also, these markers were more abundant in the tumor tissue than in the surrounding 'normal' lung tissue of NNK+LPS-induced lung tumors. PD-L1 expression in lung tumors was associated with IFNγ/STAT1/STAT3 signaling axis. In cell line models, PD-L1 expression was found to be significantly enhanced in phorbol-12-myristate 13-acetate activated THP-1 human monocytes (macrophages) treated with LPS or incubated in conditioned media (CM) generated by non-small cell lung cancer (NSCLC) cells. Similarly, when NSCLC cells were incubated in CM generated by activated THP-1 cells, PD-L1 expression was upregulated in EGFR- and ERK-dependent manner. Overall, our observations indicate that COPD-like chronic inflammation creates a favorable immunosuppressive microenvironment for tumor development and COPD-associated lung tumors might show a better response to immune checkpoint therapies.
Collapse
Affiliation(s)
| | - Yong Hwan Han
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Jung Min Song
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | | | - Pramod Upadhyaya
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Fekadu Kassie
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.,College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA
| |
Collapse
|
|
39
|
Zhou J, Chao Y, Yao D, Ding N, Li J, Gao L, Zhang Y, Xu X, Zhou J, Halmos B, Tsoukalas N, Kataoka Y, de Mello RA, Song Y, Hu J. Impact of chronic obstructive pulmonary disease on immune checkpoint inhibitor efficacy in advanced lung cancer and the potential prognostic factors. Transl Lung Cancer Res 2021; 10:2148-2162. [PMID: 34164266 PMCID: PMC8182718 DOI: 10.21037/tlcr-21-214] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 04/27/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND The coexistence of chronic obstructive pulmonary disease (COPD) in lung cancer patients often correlates with a poor clinical outcome regardless of tumor stage, mainly due to older age, poor lung function, and complex comorbid disease. Emerging data suggest that the pathogenesis of both diseases involves aberrant immune functioning. We conducted this retrospective study to describe the impact of COPD on the clinical outcomes of lung cancer patients treated with immunotherapy and investigate the potential prognostic factors. METHODS In total, 156 patients with advanced-stage lung cancer who received at least one administration of an anti-programmed cell death 1 (PD-1)/anti-programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitor (ICI) at any treatment line at Zhongshan Hospital Fudan University between May 2018 and December 2019 were enrolled in our study. Overall survival (OS) and progression-free survival (PFS) were analyzed according to the presence of COPD. We also evaluated the prognostic value of circulating cytokine levels for clinical outcome. RESULTS We found that the presence of COPD (both spirometry-based COPD and physician-defined COPD) was significantly associated with longer PFS (316 vs. 186 days, P=0.018). Moderate and severe COPD tended to have a better impact on the survival of these patients. In the present study, we reported that patients with mixed ventilatory defects tended to have a better OS (P=0.043) and PFS (P=0.18) when treated with ICIs compared to the normal lung function group. We also found that low baseline plasma interleukin (IL)-8 and IL-2 receptor (IL-2R) levels were associated with longer PFS in patients with advanced-stage lung cancer who received ICI treatment. Furthermore, patients who had increased IL-2R levels had significantly poorer OS [hazard ratio (HR) =3.63; 95% confidence interval (CI), 0.98-13.44; P=0.040] and PFS (HR =3.241; 95% CI, 1.032-10.18; P=0.035) when treated with ICIs. Nomograms were established based on the independent prognostic factors derived from our final multivariate models. CONCLUSIONS COPD was associated with better survival in advanced-stage lung cancer patients treated with ICIs. Plasma IL-8 and IL-2R levels were potential prognostic factors for clinical outcome. The nomograms represent a possibly useful tool for predicting the clinical outcomes of immunotherapy.
Collapse
Affiliation(s)
- Jiebai Zhou
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yencheng Chao
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Danwei Yao
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, USA
| | - Ning Ding
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiamin Li
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lei Gao
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yong Zhang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaobo Xu
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Balazs Halmos
- Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | | | - Yuki Kataoka
- Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan
| | - Ramon Andrade de Mello
- Faculdade de Medicina Universidade Nove de Julho (UNINOVE), Rua Pedro Oliveira Tavares, Bauru, SP, Brazil
| | - Yuanlin Song
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Hu
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
40
|
Principe N, Kidman J, Lake RA, Lesterhuis WJ, Nowak AK, McDonnell AM, Chee J. Malignant Pleural Effusions-A Window Into Local Anti-Tumor T Cell Immunity? Front Oncol 2021; 11:672747. [PMID: 33987104 PMCID: PMC8111299 DOI: 10.3389/fonc.2021.672747] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/07/2021] [Indexed: 01/01/2023] Open
Abstract
The success of immunotherapy that targets inhibitory T cell receptors for the treatment of multiple cancers has seen the anti-tumor immune response re-emerge as a promising biomarker of response to therapy. Longitudinal characterization of T cells in the tumor microenvironment (TME) helps us understand how to promote effective anti-tumor immunity. However, serial analyses at the tumor site are rarely feasible in clinical practice. Malignant pleural effusions (MPE) associated with thoracic cancers are an abnormal accumulation of fluid in the pleural space that is routinely drained for patient symptom control. This fluid contains tumor cells and immune cells, including lymphocytes, macrophages and dendritic cells, providing a window into the local tumor microenvironment. Recurrent MPE is common, and provides an opportunity for longitudinal analysis of the tumor site in a clinical setting. Here, we review the phenotype of MPE-derived T cells, comparing them to tumor and blood T cells. We discuss the benefits and limitations of their use as potential dynamic biomarkers of response to therapy.
Collapse
Affiliation(s)
- Nicola Principe
- National Centre for Asbestos Related Diseases, Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia
- School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
| | - Joel Kidman
- National Centre for Asbestos Related Diseases, Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia
- School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
| | - Richard A. Lake
- National Centre for Asbestos Related Diseases, Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia
- School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
| | - Willem Joost Lesterhuis
- School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
- Telethon Kids Institute, Perth, WA, Australia
| | - Anna K. Nowak
- National Centre for Asbestos Related Diseases, Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia
- School of Medicine, University of Western Australia, Crawley, WA, Australia
| | | | - Jonathan Chee
- National Centre for Asbestos Related Diseases, Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia
- School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
| |
Collapse
|
|
41
|
Ritzmann F, Borchardt K, Vella G, Chitirala P, Angenendt A, Herr C, Menger MD, Hoth M, Lis A, Bohle RM, Bals R, Beisswenger C. Blockade of PD-1 decreases neutrophilic inflammation and lung damage in experimental COPD. Am J Physiol Lung Cell Mol Physiol 2021; 320:L958-L968. [PMID: 33759577 DOI: 10.1152/ajplung.00121.2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Chronic obstructive lung disease (COPD) and lung cancer are both caused by smoking and often occur as comorbidity. The programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) axis is an important canonic immunoregulatory pathway, and antibodies that specifically block PD-1 or PD-L1 have demonstrated efficacy as therapeutic agents for non-small cell lung cancer. The role of the PD-1/PD-L1 axis in the pathogenesis of COPD is unknown. Here, we analyzed the function of the PD-1/PD-L1 axis in preclinical COPD models and evaluated the concentrations of PD-1 and PD-L1 in human serum and bronchoalveolar lavage (BAL) fluids as biomarkers for COPD. Anti-PD-1 treatment decreased lung damage and neutrophilic inflammation in mice chronically exposed to cigarette smoke (CS) or nontypeable Haemophilus influenzae (NTHi). Ex vivo stimulated macrophages obtained from anti-PD-1-treated mice released reduced amounts of inflammatory cytokines. PD-L1 concentrations correlated positively with PD-1 concentrations in human serum and BAL fluids. Lung sections obtained from patients with COPD stained positive for PD-L1. Our data indicate that the PD-1/PD-L1 axis is involved in developing inflammation and tissue destruction in COPD. Inflammation-induced activation of the PD-1 pathway may contribute to disease progression.
Collapse
Affiliation(s)
- Felix Ritzmann
- Department of Internal Medicine V-Pulmonology, Allergology, and Respiratory Critical Care Medicine, Saarland University, Homburg, Saarland, Germany
| | - Kai Borchardt
- Department of Internal Medicine V-Pulmonology, Allergology, and Respiratory Critical Care Medicine, Saarland University, Homburg, Saarland, Germany
| | - Giovanna Vella
- Department of Internal Medicine V-Pulmonology, Allergology, and Respiratory Critical Care Medicine, Saarland University, Homburg, Saarland, Germany
| | - Praneeth Chitirala
- Department of Internal Medicine V-Pulmonology, Allergology, and Respiratory Critical Care Medicine, Saarland University, Homburg, Saarland, Germany
| | - Adrian Angenendt
- Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Saarland, Germany
| | - Christian Herr
- Department of Internal Medicine V-Pulmonology, Allergology, and Respiratory Critical Care Medicine, Saarland University, Homburg, Saarland, Germany
| | - Michael D Menger
- Institute for Clinical and Experimental Surgery, Saarland University Medical Center, Homburg, Saarland, Germany
| | - Markus Hoth
- Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Saarland, Germany
| | - Annette Lis
- Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Saarland, Germany
| | - Rainer M Bohle
- Department of Pathology, Saarland University, Homburg, Saarland, Germany
| | - Robert Bals
- Department of Internal Medicine V-Pulmonology, Allergology, and Respiratory Critical Care Medicine, Saarland University, Homburg, Saarland, Germany
| | - Christoph Beisswenger
- Department of Internal Medicine V-Pulmonology, Allergology, and Respiratory Critical Care Medicine, Saarland University, Homburg, Saarland, Germany
| |
Collapse
|
|
42
|
Liu CH, Chen Z, Chen K, Liao FT, Chung CE, Liu X, Lin YC, Keohavong P, Leikauf GD, Di YP. Lipopolysaccharide-Mediated Chronic Inflammation Promotes Tobacco Carcinogen-Induced Lung Cancer and Determines the Efficacy of Immunotherapy. Cancer Res 2021; 81:144-157. [PMID: 33122306 PMCID: PMC7878420 DOI: 10.1158/0008-5472.can-20-1994] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/10/2020] [Accepted: 10/26/2020] [Indexed: 11/16/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that is associated with increased risk of lung cancer. Pseudomonas aeruginosa (PA) infections are frequent in patients with COPD, which increase lung inflammation and acute exacerbations. However, the influences of PA-induced inflammation on lung tumorigenesis and the efficacy of immune checkpoint blockade remain unknown. In this study, we initiated a murine model of lung cancer by treating FVB/NJ female mice with tobacco carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) alone or in combination with PA-lipopolysaccharide (LPS). LPS-mediated chronic inflammation induced T-cell exhaustion, increased the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis, and enhanced NNK-induced lung tumorigenesis through an immunosuppressive microenvironment characterized by accumulation of myeloid-derived suppressive cells (MDSC) and regulatory T cells. Anti-PD-1 antibody treatment reduced tumors in NNK/LPS-treated mice with a 10-week LPS treatment but failed to inhibit tumor growth when LPS exposure was prolonged to 16 weeks. Anti-Ly6G antibody treatment coupled with depletion of MDSC alone reduced tumor growth; when combined with anti-PD-1 antibody, this treatment further enhanced antitumor activity in 16-week NNK/LPS-treated mice. Immune gene signatures from a human lung cancer dataset of PD-1 blockade were identified, which predicted treatment responses and survival outcome and overlapped with those from the mouse model. This study demonstrated that LPS-mediated chronic inflammation creates a favorable immunosuppressive microenvironment for tumor progression and correlates with the efficacy of anti-PD-1 treatment in mice. Immune gene signatures overlap with human and mouse lung tumors, providing potentially predictive markers for patients undergoing immunotherapy. SIGNIFICANCE: This study identifies an immune gene signature that predicts treatment responses and survival in patients with tobacco carcinogen-induced lung cancer receiving immune checkpoint blockade therapy.
Collapse
Affiliation(s)
- Chia-Hsin Liu
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Zhong Chen
- Tumor Biology Section and Clinical Genomics Unit, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Kong Chen
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Fu-Tien Liao
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Chia-En Chung
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Xiaoping Liu
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
- Medical College of Qingdao University, Shandong Province, China
| | - Yu-Chun Lin
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Phouthone Keohavong
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - George D Leikauf
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Yuanpu Peter Di
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
| |
Collapse
|
|
43
|
Lim JU, Kang HS, Yeo CD, Kim JS, Park CK, Kim YH, Kim JW, Kim SJ, Lee SH. Impact of Combined Chronic Obstructive Pulmonary Disease Status and Systemic Inflammation on Outcome of Advanced NSCLC: Multicenter Retrospective Cohort Study. Int J Chron Obstruct Pulmon Dis 2020; 15:3323-3334. [PMID: 33363365 PMCID: PMC7753914 DOI: 10.2147/copd.s274354] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 11/16/2020] [Indexed: 01/01/2023] Open
Abstract
Background In patients with non-small cell lung cancer (NSCLC), both chronic obstructive pulmonary disease (COPD) and systemic inflammatory biomarkers, such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), have significant association with prognosis. NLR and PLR also predict mortality in patients with COPD alone. A combination of the two parameters may be helpful in a more individualized approach for predicting prognosis in NSCLC. Methods Medical records of patients with stage IIIB and IV NSCLC from January 2012 to January 2018 in seven university hospitals were reviewed. Patients were categorized into four subgroups based on pulmonary function test results and cutoffs for NLR or PLR. Results A total of 277 patients were evaluated and categorized into non-COPD and COPD groups; 194 patients were in the non-COPD group and 83 patients were in the COPD group. The non-COPD group showed significantly longer overall survival (OS) compared with the COPD group (P = 0.019). Median survival was significantly different between high/low PLR groups (P < 0.001), between high/low NLR groups (P = 0.001), and between high/low c-reactive protein (CRP) groups (P < 0.001). PLR, NLR and CRP showed significant correlations with each other. PLR showed a significant negative linear correlation with FVC (absolute) (r = −0.149, P = 0.015), FVC (%) (r = −0.192, P = 0.002), DLCO (absolute) (r = −0.271, P < 0.001), DLCO (%) (r = −0.139, P = 0.032), and NLR (r = 0.718, P < 0.001). In the multivariate analysis, the high PLR, COPD sub-group showed significantly higher risk for mortality (HR 2.066 (1.175–3.633), P = 0.012) compared with the low-PLR non-COPD group. However, COPD-NLR subtype was not an independent predictor for OS. Conclusion A combination of COPD status and PLR may be a cost-effective and readily available prognostic marker in patients with advanced NSCLC.
Collapse
Affiliation(s)
- Jeong Uk Lim
- Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hye Seon Kang
- Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Chang Dong Yeo
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ju Sang Kim
- Division of Pulmonary, Critical Care and Sleep Allergy, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chan Kwon Park
- Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yong Hyun Kim
- Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Jin Woo Kim
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Joon Kim
- Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang Haak Lee
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| |
Collapse
|
|
44
|
Meziane O, Alexandrova Y, Olivenstein R, Dupuy FP, Salahuddin S, Thomson E, Orlova M, Schurr E, Ancuta P, Durand M, Chomont N, Estaquier J, Bernard NF, Costiniuk CT, Jenabian MA. Peculiar Phenotypic and Cytotoxic Features of Pulmonary Mucosal CD8 T Cells in People Living with HIV Receiving Long-Term Antiretroviral Therapy. THE JOURNAL OF IMMUNOLOGY 2020; 206:641-651. [PMID: 33318292 DOI: 10.4049/jimmunol.2000916] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 11/13/2020] [Indexed: 12/31/2022]
Abstract
People living with HIV have high burdens of chronic lung disease, lung cancers, and pulmonary infections despite antiretroviral therapy (ART). The rates of tobacco smoking by people living with HIV vastly exceed that of the general population. Furthermore, we showed that HIV can persist within the lung mucosa despite long-term ART. As CD8 T cell cytotoxicity is pivotal for controlling viral infections and eliminating defective cells, we explored the phenotypic and functional features of pulmonary versus peripheral blood CD8 T cells in ART-treated HIV+ and uninfected controls. Bronchoalveolar lavage fluid and matched blood were obtained from asymptomatic ART-treated HIV+ smokers (n = 11) and nonsmokers (n = 15) and uninfected smokers (n = 7) and nonsmokers (n = 10). CD8 T cell subsets and phenotypes were assessed by flow cytometry. Perforin/granzyme B content, degranulation (CD107a expression), and cytotoxicity against autologous Gag peptide-pulsed CD4 T cells (Annexin V+) following in vitro stimulation were assessed. In all groups, pulmonary CD8 T cells were enriched in effector memory subsets compared with blood and displayed higher levels of activation (HLA-DR+) and exhaustion (PD1+) markers. Significant reductions in proportions of senescent pulmonary CD28-CD57+ CD8 T cells were observed only in HIV+ smokers. Pulmonary CD8 T cells showed lower perforin expression ex vivo compared with blood CD8 T cells, with reduced granzyme B expression only in HIV+ nonsmokers. Bronchoalveolar lavage CD8 T cells showed significantly less in vitro degranulation and CD4 killing capacity than blood CD8 T cells. Therefore, pulmonary mucosal CD8 T cells are more differentiated, activated, and exhausted, with reduced killing capacity in vitro than blood CD8 T cells, potentially contributing to a suboptimal anti-HIV immune response within the lungs.
Collapse
Affiliation(s)
- Oussama Meziane
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Département des Sciences Biologiques, Université du Québec à Montréal, Montreal, Quebec H2X 1Y4, Canada
| | - Yulia Alexandrova
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Département des Sciences Biologiques, Université du Québec à Montréal, Montreal, Quebec H2X 1Y4, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada
| | - Ronald Olivenstein
- Division of Respirology, Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada
| | - Franck P Dupuy
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada
| | - Syim Salahuddin
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Département des Sciences Biologiques, Université du Québec à Montréal, Montreal, Quebec H2X 1Y4, Canada
| | - Elaine Thomson
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Département des Sciences Biologiques, Université du Québec à Montréal, Montreal, Quebec H2X 1Y4, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada
| | - Marianna Orlova
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada
| | - Erwin Schurr
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Department of Human Genetics, McGill University, Montreal, Quebec H3A 0C7, Canada
| | - Petronela Ancuta
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 0A9, Canada.,Département de Microbiologie, Infectiologie, et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
| | - Madeleine Durand
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 0A9, Canada
| | - Nicolas Chomont
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 0A9, Canada.,Département de Microbiologie, Infectiologie, et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
| | - Jérôme Estaquier
- Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine, Université Laval, Quebec City, Quebec G1V 4G2, Canada
| | - Nicole F Bernard
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Division of Experimental Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada.,Division of Clinical Immunology, McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada; and
| | - Cecilia T Costiniuk
- Infectious Diseases and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada.,Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Division of Infectious Diseases, McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada
| | - Mohammad-Ali Jenabian
- Département des Sciences Biologiques, Université du Québec à Montréal, Montreal, Quebec H2X 1Y4, Canada; .,Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada.,Département de Microbiologie, Infectiologie, et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
| |
Collapse
|
|
45
|
Russick J, Joubert PE, Gillard-Bocquet M, Torset C, Meylan M, Petitprez F, Dragon-Durey MA, Marmier S, Varthaman A, Josseaume N, Germain C, Goc J, Dieu-Nosjean MC, Validire P, Fournel L, Zitvogel L, Bindea G, Lupo A, Damotte D, Alifano M, Cremer I. Natural killer cells in the human lung tumor microenvironment display immune inhibitory functions. J Immunother Cancer 2020; 8:jitc-2020-001054. [PMID: 33067317 PMCID: PMC7570244 DOI: 10.1136/jitc-2020-001054] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Natural killer (NK) cells play a crucial role in tumor immunosurveillance through their cytotoxic effector functions and their capacity to interact with other immune cells to build a coordinated antitumor immune response. Emerging data reveal NK cell dysfunction within the tumor microenvironment (TME) through checkpoint inhibitory molecules associated with a regulatory phenotype. OBJECTIVE We aimed at analyzing the gene expression profile of intratumoral NK cells compared with non-tumorous NK cells, and to characterize their inhibitory function in the TME. METHODS NK cells were sorted from human lung tumor tissue and compared with non- tumoral distant lungs. RESULTS In the current study, we identify a unique gene signature of NK cell dysfunction in human non-small cell lung carcinoma (NSCLC). First, transcriptomic analysis reveals significant changes related to migratory pattern with a downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) and CX3C chemokine receptor 1 (CX3CR1) and overexpression of C-X-C chemokine receptor type 5 (CXCR5) and C-X-C chemokine receptor type 6 (CXCR6). Second, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and killer cell lectin like receptor (KLRC1) inhibitory molecules were increased in intratumoral NK cells, and CTLA-4 blockade could partially restore MHC class II level on dendritic cell (DC) that was impaired during the DCs/NK cell cross talk. Finally, NK cell density impacts the positive prognostic value of CD8+ T cells in NSCLC. CONCLUSIONS These findings demonstrate novel molecular cues associated with NK cell inhibitory functions in NSCLC.
Collapse
Affiliation(s)
- Jules Russick
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France
| | - Pierre-Emmanuel Joubert
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France
| | - Mélanie Gillard-Bocquet
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France
| | - Carine Torset
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France
| | - Maxime Meylan
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France
| | - Florent Petitprez
- Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
| | - Marie-Agnes Dragon-Durey
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France.,Universite de Paris. Laboratoire d'immunologie, Hopital Europeen Georges Pompidou, APHP, Paris, France
| | - Solenne Marmier
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France
| | - Aditi Varthaman
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France
| | - Nathalie Josseaume
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France
| | - Claire Germain
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France
| | - Jérémy Goc
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France
| | - Marie-Caroline Dieu-Nosjean
- Sorbonne Universite, INSERM U1135, Centre d'Immunologie et des Maladies Infectieuses, Team Immune Microenvironment and Immunotherapy, F-75013, Paris, France
| | - Pierre Validire
- Department of Pathology, Institut Mutualiste Montsouris, Paris, France
| | - Ludovic Fournel
- Departments of Pathology and Thoracic Surgery, Hospital Cochin Assistance Publique Hopitaux de Paris, F-75014, Paris, France
| | - Laurence Zitvogel
- INSERM U1015, Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France.,Universite Paris Saclay, Le Kremlin-Bicêtre, France
| | - Gabriela Bindea
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Laboratory of Integrative cancer immunology, F-75006, Paris, France
| | - Audrey Lupo
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France.,Departments of Pathology and Thoracic Surgery, Hospital Cochin Assistance Publique Hopitaux de Paris, F-75014, Paris, France
| | - Diane Damotte
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France.,Departments of Pathology and Thoracic Surgery, Hospital Cochin Assistance Publique Hopitaux de Paris, F-75014, Paris, France
| | - Marco Alifano
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France.,Departments of Pathology and Thoracic Surgery, Hospital Cochin Assistance Publique Hopitaux de Paris, F-75014, Paris, France
| | - Isabelle Cremer
- Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, complement and cancer, F-75006, Paris, France
| |
Collapse
|
|
46
|
B Cells and Tertiary Lymphoid Structures Influence Survival in Lung Cancer Patients with Resectable Tumors. Cancers (Basel) 2020; 12:cancers12092644. [PMID: 32947928 PMCID: PMC7564217 DOI: 10.3390/cancers12092644] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 08/31/2020] [Accepted: 09/11/2020] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Nowadays, humans still die of lung cancer (LC), a disease mainly related to cigarette smoking (CS). Smokers also develop chronic bronchitis, namely chronic obstructive pulmonary disease (COPD). Environmental factors and a natural predisposition from the patients’ sides may render them more prone to develop tumors derived from CS. Thus, a great number of patients may suffer from chronic bronchitis and LC simultaneously. Chronic respiratory diseases are also important risks factors for LC. The immune system, among other biological mechanisms, protect our cells from infections and cancer development. Several immune structures and cells may be altered in the tumors of patients with COPD as opposed to lung tumors of patients with no underlying respiratory disease. A total of 133 patients with LC participated in the study: 93 with underlying COPD. Several structures (tertiary lymphoid structures, TLS) and T and B lymphocytes were analyzed in the lung tumor and non-tumor areas (specimens obtained during surgical extirpation of the tumors). We found that in LC patients with COPD, compared to those without it, fewer numbers of TLSs and B cells were detected, and those patients died significantly earlier. These results have implications in the diagnosis and treatment options of lung tumors in patients with underlying respiratory diseases. Abstract Immune profile of B and T cells and tertiary lymphoid structures (TLSs) may differ in tumors of lung cancer (LC) patients with/without chronic obstructive pulmonary disease (COPD), and may also influence patient survival. We sought to analyze: (1) TLSs, germinal centers (GCs), B and T cells, and (2) associations of the immune biomarkers with the patients’ 10-year overall survival (OS). TLSs (numbers and area), B [cluster of differentiation (CD) 20], and T (CD3), and GCs cells were identified in both tumor and non-tumor specimens (thoracotomy) from 90 LC-COPD patients and 43 LC-only patients. Ten-year OS was analyzed in the patients. Immune profile in tumors of LC-COPD versus LC: TLS numbers and areas significantly decreased in tumors of LC-COPD compared to LC patients. No significant differences were observed in tumors between LC-COPD and LC patients for B or T cells. Immune profile in tumors versus non-tumor specimens: TLS areas and B cells significantly increased, T cells significantly decreased in tumors of both LC and LC-COPD patients. Survival: in LC-COPD patients: greater area of TLSs and proportion of B cells were associated with longer survival rates. The immune tumor microenvironment differs in patients with underlying COPD and these different phenotypes may eventually impact the response to immunotherapy in patients with LC.
Collapse
|
|
47
|
Prieto M, Bobbio A, Fournel L, Icard P, Canny EH, Mansuet Lupo A, Leroy K, Wislez M, Damotte D, Alifano M. [Surgical management of resectable non-small cell lung cancer: Towards new paradigms]. Bull Cancer 2020; 107:904-911. [PMID: 32674934 DOI: 10.1016/j.bulcan.2020.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 04/21/2020] [Accepted: 05/11/2020] [Indexed: 10/23/2022]
Abstract
Adapting therapies and providing personalized care for patients with resectable non-small cell lung cancer represent major challenges. This involves integrating several parameters into the patient's management, not only crude pathologic results, but also a better understanding of the mechanisms involved in tumor progression. Many studies have looked at the impact of host and tumor characteristics and their interactions through inflammatory processes or tumor immune environment. Beyond tumor stage, poor nutrition, sarcopenia and inflammatory state have been identified as independent factors that can directly impact postoperative outcome. The development of Enhanced Recovery After Surgery (ERAS), in which patient becomes the main player in their own management, seems to be an interesting answer since it seems to allow a reduction in postoperative complications, length of stay and indirectly reduction in costs. A broader and more complete vision including morphometric evaluation of the patient, physical performances, inflammatory state and nutritional state would provide additional discriminating information which can predict postoperative outcome and help in adapting therapies in a personalized way.
Collapse
Affiliation(s)
- Mathilde Prieto
- AP-HP Centre, UNIVERSITE de Paris, hôpital Cochin, service de chirurgie thoracique, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France
| | - Antonio Bobbio
- AP-HP Centre, UNIVERSITE de Paris, hôpital Cochin, service de chirurgie thoracique, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France
| | - Ludovic Fournel
- AP-HP Centre, UNIVERSITE de Paris, hôpital Cochin, service de chirurgie thoracique, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France
| | - Philippe Icard
- AP-HP Centre, UNIVERSITE de Paris, hôpital Cochin, service de chirurgie thoracique, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France
| | - Emelyne Hamelin Canny
- AP-HP Centre, UNIVERSITE de Paris, hôpital Cochin, service de chirurgie thoracique, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France
| | - Audrey Mansuet Lupo
- AP-HP Centre, université de Paris, hôpital Cochin, service de pathologie, Paris, France
| | - Karen Leroy
- AP-HP Centre, université de Paris, hôpital Cochin, service de génétique et biologie moléculaire, Paris, France
| | - Marie Wislez
- AP-HP Centre, université de Paris, hôpital Cochin, service de pneumologie, Paris, France
| | - Diane Damotte
- AP-HP Centre, université de Paris, hôpital Cochin, service de pathologie, Paris, France
| | - Marco Alifano
- AP-HP Centre, UNIVERSITE de Paris, hôpital Cochin, service de chirurgie thoracique, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France.
| |
Collapse
|
|
48
|
Alifano M. Systemic immune-inflammation index and prognosis of advanced non-small cell lung cancer. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:667. [PMID: 32617287 PMCID: PMC7327370 DOI: 10.21037/atm.2020.03.174] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Marco Alifano
- Department of Thoracic Surgery, Cochin Hospital, AP-HP Centre - University of Paris, Paris, France.,Team Cancer, Immune Control and Escape, INSERM U1138, Cordeliers Research Center, Paris, France
| |
Collapse
|
|
49
|
Akamine T, Tagawa T, Mori M. Relationship between obstructive lung disease and non-small cell lung cancer. J Thorac Dis 2020; 12:1145-1146. [PMID: 32274190 PMCID: PMC7139003 DOI: 10.21037/jtd.2019.12.09] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Takaki Akamine
- Department of Surgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan
| | - Tetsuzo Tagawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| |
Collapse
|
|
50
|
Abstract
Biomarkers that focus on lung cancer risk assessment, detection, prognosis, diagnosis, and personalized treatment are in various stages of development. This article provides an overview of lung cancer biomarker development, focusing on clinical utility and highlighting 2 unmet clinical needs: selection of high-risk patients for lung cancer screening and differentiation of early lung cancer from benign pulmonary nodules. The authors highlight biomarkers under development and those lung cancer screening and nodule management biomarkers post-clinical validation. Finally, trends in lung cancer biomarker development that may improve accuracy and accelerate implementation in practice are discussed.
Collapse
|