Lung cancer is the leading cause of cancer-related death. While the recent introduction of immune checkpoint immunotherapies significantly improves patient outcome, many do not respond to this treatment. Dendritic cells (DCs) activate CD8+ T cells to promote the anticancer immune response. Also, in mice, pulmonary CD103+ DC1s specialize in tumour antigen presentation. However, cancer induces an immunosuppressive microenvironment that alters immune function to promote tumor development. Yet, the impact of lung tumor development on DCs remains misunderstood. To study the impact of lung tumour development on the lung dendritic cell signature, Lewis lung carcinoma (LLC) and B16F10 cells (melanoma lung metastasis) were injected intravenously, and lung DC populations analysed by flow cytometry. We observed that in cancer, the proportions of CD103+ DC1 are largely reduced, while an uncharacterized lung CD103+CD11b+ DC population is induced. The latest express surface markers and transcription factors associated with the DC2 population and high levels of PD-L1 and PD-L2 regulatory molecules. This is of crucial importance to immune checkpoint inhibitor therapies, as they rely on the efficient presentation of tumour antigen by DCs to induce T cell responses. In order to promote the anti-tumor capacity of the DC signature, CD103+ DC1s were injected in combination with an immune checkpoint inhibitor (anti-PD-1) in the B16F10 model of resistance to anti-PD1 therapy. The co-injection led to improved sensitivity to immunotherapy. Thus, promoting the replenishment of an anticancer DC environment could be an interesting therapeutic avenue to increase the efficiency of existing immune checkpoint inhibitor therapies.
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.
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