Downregulation of Membrane Trafficking Proteins and Lactate Conditioning Determine Loss of Dendritic Cell Function in Lung Cancer.

Abstract

Restoring antigen presentation for efficient and durable activation of tumor-specific CD8+ T-cell responses is pivotal to immunotherapy, yet the mechanisms that cause subversion of dendritic cell (DC) functions are not entirely understood, limiting the development of targeted approaches. In this study, we show that bona fide DCs resident in lung tumor tissues or DCs exposed to factors derived from whole lung tumors become refractory to endosomal and cytosolic sensor stimulation and fail to secrete IL12 and IFNI. Tumor-conditioned DC exhibited downregulation of the SNARE VAMP3, a regulator of endosomes trafficking critical for cross-presentation of tumor antigens and DC-mediated tumor rejection. Dissection of cell-extrinsic suppressive pathways identified lactic acid in the tumor microenvironment as sufficient to inhibit type-I IFN downstream of TLR3 and STING. DC conditioning by lactate also impacted adaptive function, accelerating antigen degradation and impairing cross-presentation. Importantly, DCs conditioned by lactate failed to prime antitumor responses in vivo These findings provide a new mechanistic viewpoint to the concept of DC suppression and hold potential for future therapeutic approaches.Significance: These findings provide insight into the cell-intrinsic and cell-extrinsic mechanisms that cause loss of presentation of tumor-specific antigens in lung cancer tissues. Cancer Res; 78(7); 1685-99. ©2018 AACR.

• Authors: Nicoletta Caronni, Francesca Simoncello, Francesca Stafetta, Corrado Guarnaccia, Juan Sebastian Ruiz-Moreno, Bastian Opitz, Thierry Galli, Veronique Proux-Gillardeaux, Federica Benvenuti
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 7 Pg. 1685-1699 (04 01 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29363545 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antigens, Neoplasm
• Culture Media, Conditioned
• Interferon Type I
• Membrane Transport Proteins
• SNARE Proteins
• Vesicle-Associated Membrane Protein 3
• vesicle-associated membrane protein 3, mouse
• Lactic Acid

Topics

• Animals
• Antigen Presentation (immunology)
• Antigens, Neoplasm (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Culture Media, Conditioned (metabolism)
• Dendritic Cells (immunology)
• Down-Regulation
• Endosomes (metabolism)
• Immunotherapy
• Interferon Type I (antagonists & inhibitors)
• Lactic Acid (metabolism)
• Lung Neoplasms (immunology, pathology)
• Membrane Transport Proteins (biosynthesis)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• SNARE Proteins (biosynthesis)
• Tumor Microenvironment (immunology)
• Vesicle-Associated Membrane Protein 3 (biosynthesis)