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.
Highlights
Lung cancer remains the most lethal cancer in industrialized countries
The percentage of lung CD103+XCR1+ DC1s gradually decreased and reciprocally, the percentage of CD11b+Sirpα+ DC2s increased slightly in both models (Fig 1C–1E). These results indicate that tumor development impacts the balance between CD103+XCR1+ DC1s and CD11b+Sirpα+ DC2s at the expense of the antitumor DC1 population
The presence and activity of pre-existing CD8 T cells that are specific to tumor antigens is an essential condition for the success of immune checkpoint inhibitor (ICI)
Summary
Lung cancer remains the most lethal cancer in industrialized countries. Despite significant advances in conventional therapies, the five-year survival rate remains lower than 20%. The contribution of DC2s in anticancer immune response is not well established, but some propose they are necessary to induce antitumor CD4 T cell immunity [18] Despite this wealth of knowledge on anticancer immune responses, lung cancer immunotherapy remains weakly effective [3, 6]. This may stem in part from the current lack of knowledge on the impact of lung cancer on local DC populations, which are crucial in anticancer immunity. These results suggest that lung tumor progression alters the local DC population signature to favour tumor growth and underline new mechanisms explaining the inability of the local DC1s to naturally regulate tumor growth, and possible resistance to anti-PD-1 therapies
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