1. Countering the advert effects of lung cancer on the anticancer potential of dendritic cell populations reinstates sensitivity to anti-PD-1 therapy
- Author
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Emilie Bernatchez, Marie-Renée Blanchet, David Marsolais, Meredith Elizabeth Gill, Julyanne Brassard, Philippe Joubert, Joanny Roy, and Véronique Desjardins
- Subjects
Male ,Lung Neoplasms ,Skin Neoplasms ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Melanoma, Experimental ,Cancer Treatment ,Lung and Intrathoracic Tumors ,Carcinoma, Lewis Lung ,Mice ,White Blood Cells ,Spectrum Analysis Techniques ,Animal Cells ,Medicine and Health Sciences ,Neoplasm Metastasis ,Immune Checkpoint Inhibitors ,Immune Response ,Skin Tumors ,Multidisciplinary ,T Cells ,Flow Cytometry ,Neoplasm Proteins ,Oncology ,Spectrophotometry ,Medicine ,Female ,Cytophotometry ,Cellular Types ,Research Article ,Immune Cells ,Science ,Immunology ,Cytotoxic T cells ,chemical and pharmacologic phenomena ,Dermatology ,Research and Analysis Methods ,Immune system ,medicine ,Animals ,Lung cancer ,Blood Cells ,business.industry ,Cancer ,Lewis lung carcinoma ,Cancers and Neoplasms ,Biology and Life Sciences ,Immunotherapy ,Dendritic cell ,Dendritic Cells ,Cell Biology ,medicine.disease ,Immune checkpoint ,Cancer cell ,Cancer research ,Secondary Lung Tumors ,business - Abstract
Lung cancer is the leading cause of cancer-related deaths. While the recent use of immune checkpoint inhibitors significantly improves patient outcomes, responsiveness remains restricted to a small proportion of patients. Conventional dendritic cells (DCs) play a major role in anticancer immunity. In mice, two subpopulations of DCs are found in the lung: DC2s (CD11b+Sirpα+) and DC1s (CD103+XCR1+), the latest specializing in the promotion of anticancer immune responses. However, the impact of lung cancer on DC populations and the consequent influence on the anticancer immune response remain poorly understood. To address this, DC populations were studied in murine models of Lewis Lung Carcinoma (LLC) and melanoma-induced lung metastasis (B16F10). We report that direct exposure to live or dead cancer cells impacts the capacity of DCs to differentiate into CD103+ DC1s, leading to profound alterations in CD103+ DC1 proportions in the lung. In addition, we observed the accumulation of CD103loCD11b+ DCs, which express DC2 markers IRF4 and Sirpα, high levels of T-cell inhibitory molecules PD-L1/2 and the regulatory molecule CD200. Finally, DC1s were injected in combination with an immune checkpoint inhibitor (anti-PD-1) in the B16F10 model of resistance to the anti-PD-1 immune checkpoint therapy; the co-injection restored sensitivity to immunotherapy. Thus, we demonstrate that lung tumor development leads to the accumulation of CD103loCD11b+ DCs with a regulatory potential combined with a reduced proportion of highly-specialized antitumor CD103+ DC1s, which could promote cancer growth. Additionally, promoting an anticancer DC signature could be an interesting therapeutic avenue to increase the efficacy of existing immune checkpoint inhibitors.
- Published
- 2021