Recent studies highlighted the essential role of tissue-resident dendritic cells (DCs) for T cells priming and immune checkpoint therapy, however the mechanism leading to DCs suppression during tumor growth are still poorly understood. Here we have isolated CD103 (DC1) and Cd11b (DC2) from orthotopic Kras/Trp53 adenocarcinomas to study their function and gene expression profiles. At early stages of tumor progression (day 14-21) DC1 effectively cross-presented tumor antigens acquired in vivo and this was paralleled by the presence of IFN-γ; secreting tumor specific CD8+ T cells in the lung. Starting from day 28 post tumor inoculation, despite minor changes in tumor burden, DC1 were no longer able to cross present tumor associated antigens and CD8+ T cell responses were concomitantly shut-off. DC1 isolated from tumor bearing lungs and fed with antigen ex-vivo confirmed a selective loss in cross-presentation. In parallel, DC2 skewed their cytokine profile and acquired a Th17 promoting phenotype mediated by high production of IL-23. In order to identify factors causing the sudden loss in DC1 activity we analyzed gene expression profiles in total lung tissues. At day 21 we observed a peak in T cell attracting chemokines together with expression of inhibitory pathways. This signature was dramatically modified at day 28, with a decrease in T cell associated genes and an increase in neutrophils related transcripts. Gene expression profiles in de-activated DC1 showed modulation of transcripts related to innate activation and antigen processing. In summary, this study identifies a narrow temporal window during which tissue resident DCs lose the ability to cross-present tumor associated antigens. Loss of DC1 function is accompanied by cell-intrinsic changes in gene expression, cell extrinsic changes in the tumor microenvironment and loss of activity in endogenous CD8+ T antitumor responses.
Citation Format: Nicoletta Caronni, Francesca Simoncello, Karla Cervantes-Luevano, Licio Collavin, Federica Benvenuti. Loss of cross-presentation by tissue resident DC1 in lung adenocarcinomas is an early event that correlates to exhaustion of endogenous antitumor CD8+ T cell responses [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B75.