Countering the advert effects of lung cancer on the anticancer potential of dendritic cell populations reinstates sensitivity to anti-PD-1 therapy

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.

Updates on the Importance of CD200:CD200R Checkpoint Blockade in Solid Tumors and B cell Malignancies

“…A similar result showing therapeutic efficacy of CD200 blockade in reducing Merkel cell carcinoma tumor growth was seen in tumors which were infiltrated by suppressive CD200+ macrophages and Tregs [84]. Along similar lines, in animal models of lung cancer, within the TME there was preferential differentiation of DCs away from CD103+ DC1s, which have the ability to induce tumor immunity, towards CD103loCD11b+ DCs, expressing the DC2 markers IRF4 and Sirpα, along with high levels of T-cell inhibitory molecules PD-L1/2 and CD200 [85]. The effect of CD200 blockade on DC differentiation within the tumor was not investigated in these studies-see also [86].…”