Jérôme Biton1,2,3, Hanane Ouakrim1,2,3,4, Agnès Dechartres5,6,7, Marco Alifano2,8, Audrey Mansuet-Lupo1,2,3,4, Han Si9, Rebecca Halpin9, Todd Creasy9, Claudie Bantsimba-Malanda1,2,3,9, Jennifer Arrondeau2,10, François Goldwasser2,10, Pascaline Boudou-Rouquette2,10, Ludovic Fournel2,8, Nicolas Roche11, Pierre-Régis Burgel11, Jeremy Goc1,2,3, Priyanka Devi-Marulkar1,2,3, Claire Germain1,2,3, Marie-Caroline Dieu-Nosjean1,2,3, Isabelle Cremer1,2,3, Ronald Herbst9, Diane Damotte1,2,3,4. 1. 1 Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS 1138, Cordeliers Research Center, Team Cancer, Immune Control and Escape, Paris, France. 2. 2 Paris Descartes-Paris 5 University, Paris, France. 3. 3 Pierre et Marie Curie-Paris 6 University, Paris, France. 4. 4 Department of Pathology. 5. 5 Department of Clinical Epidemiology, Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France. 6. 6 METHODS Team, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité, UMR1153, INSERM, Paris, France. 7. 7 Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Service de Biostatistique Santé Publique Information Médicale, Hôpital Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; and. 8. 8 Department of Thoracic Surgery. 9. 9 Oncology Research, MedImmune, LLC, Gaithersburg, Maryland. 10. 10 Department of Medical Oncology, and. 11. 11 Department of Respiratory and Intensive Care Medicine, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
Abstract
RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) have a higher prevalence of lung cancer. The chronic inflammation associated with COPD probably promotes the earliest stages of carcinogenesis. However, once tumors have progressed to malignancy, the impact of COPD on the tumor immune microenvironment remains poorly defined, and its effects on immune-checkpoint blockers' efficacy are still unknown. OBJECTIVES: To study the impact of COPD on the immune contexture of non-small cell lung cancer. METHODS: We performed in-depth immune profiling of lung tumors by immunohistochemistry and we determined its impact on patient survival (n = 435). Tumor-infiltrating T lymphocyte (TIL) exhaustion by flow cytometry (n = 50) was also investigated. The effectiveness of an anti-PD-1 (programmed cell death-1) treatment (nivolumab) was evaluated in 39 patients with advanced-stage non-small cell lung cancer. All data were analyzed according to patient COPD status. MEASUREMENTS AND MAIN RESULTS: Remarkably, COPD severity is positively correlated with the coexpression of PD-1/TIM-3 (T-cell immunoglobulin and mucin domain-containing molecule-3) by CD8 T cells. In agreement, we observed a loss of CD8 T cell-associated favorable clinical outcome in COPD+ patients. Interestingly, a negative prognostic value of PD-L1 (programmed cell death ligand 1) expression by tumor cells was observed only in highly CD8 T cell-infiltrated tumors of COPD+ patients. Finally, data obtained on 39 patients with advanced-stage non-small cell lung cancer treated by an anti-PD-1 antibody showed longer progression-free survival in COPD+ patients, and also that the association between the severity of smoking and the response to nivolumab was preferentially observed in COPD+ patients. CONCLUSIONS: COPD is associated with an increased sensitivity of CD8 tumor-infiltrating T lymphocytes to immune escape mechanisms developed by tumors, thus suggesting a higher sensitivity to PD-1 blockade in patients with COPD.
RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) have a higher prevalence of lung cancer. The chronic inflammation associated with COPD probably promotes the earliest stages of carcinogenesis. However, once tumors have progressed to malignancy, the impact of COPD on the tumor immune microenvironment remains poorly defined, and its effects on immune-checkpoint blockers' efficacy are still unknown. OBJECTIVES: To study the impact of COPD on the immune contexture of non-small cell lung cancer. METHODS: We performed in-depth immune profiling of lung tumors by immunohistochemistry and we determined its impact on patient survival (n = 435). Tumor-infiltrating T lymphocyte (TIL) exhaustion by flow cytometry (n = 50) was also investigated. The effectiveness of an anti-PD-1 (programmed cell death-1) treatment (nivolumab) was evaluated in 39 patients with advanced-stage non-small cell lung cancer. All data were analyzed according to patientCOPD status. MEASUREMENTS AND MAIN RESULTS: Remarkably, COPD severity is positively correlated with the coexpression of PD-1/TIM-3 (T-cell immunoglobulin and mucin domain-containing molecule-3) by CD8 T cells. In agreement, we observed a loss of CD8 T cell-associated favorable clinical outcome in COPD+ patients. Interestingly, a negative prognostic value of PD-L1 (programmed cell death ligand 1) expression by tumor cells was observed only in highly CD8 T cell-infiltrated tumors of COPD+ patients. Finally, data obtained on 39 patients with advanced-stage non-small cell lung cancer treated by an anti-PD-1 antibody showed longer progression-free survival in COPD+ patients, and also that the association between the severity of smoking and the response to nivolumab was preferentially observed in COPD+ patients. CONCLUSIONS:COPD is associated with an increased sensitivity of CD8tumor-infiltrating T lymphocytes to immune escape mechanisms developed by tumors, thus suggesting a higher sensitivity to PD-1 blockade in patients with COPD.
Authors: Felix Ritzmann; Kai Borchardt; Giovanna Vella; Praneeth Chitirala; Adrian Angenendt; Christian Herr; Michael D Menger; Markus Hoth; Annette Lis; Rainer M Bohle; Robert Bals; Christoph Beisswenger Journal: Am J Physiol Lung Cell Mol Physiol Date: 2021-03-24 Impact factor: 5.464
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Authors: Jiebai Zhou; Yencheng Chao; Danwei Yao; Ning Ding; Jiamin Li; Lei Gao; Yong Zhang; Xiaobo Xu; Jian Zhou; Balazs Halmos; Nikolaos Tsoukalas; Yuki Kataoka; Ramon Andrade de Mello; Yuanlin Song; Jie Hu Journal: Transl Lung Cancer Res Date: 2021-05