Type I interferon activates MHC class I-dressed CD11b+ conventional dendritic cells to promote protective anti-tumor CD8+ T cell immunity

Duong, Ellen; Fessenden, Tim; Lutz, Emi A.; Dinter, Teresa; Yim, Leon; Blatt, Sarah E.; Bhutkar, Arjun; Wittrup, K. Dane; Spranger, Stefani

doi:10.1016/j.immuni.2021.10.020

Cited by 172 publications

(134 citation statements)

References 95 publications

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“…Albeit recently accused for secondary resistance to immunotherapy, type I IFNs are well known for their anti-tumor functions [51]. They specifically keep cDCs at a poised homeostatic state [52] and stimulate cDC maturation and LN migration upon perturbation.…”

Section: Discussionmentioning

confidence: 99%

Interferon-induced lysosomal membrane permeabilization and death cause cDC1-deserts in tumors

Aerakis

Chatzigeorgiou

Kerdidani

et al. 2022

Preprint

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The landscape of migratory conventional dendritic cells (cDCs) comprises XCR1+CD11b- cDC1s, XCR1-CD11b+ cDC2s and intermediate XCR1low/negCD11b- states. cDC1 are unique in their ability to cross-prime lymph node CD8 T cells in a CD4 T cell-dependent manner. In perturbed cancer states cDC1s become particularly scarce in tumors and tumor draining lymph nodes, which decreases T cell infiltration, immunotherapy responses and patient survival. The causes of cDC1 paucity are not fully understood and no specific therapy currently exists. Here, we find that cDC1s undergo apoptosis in tumor microenvironments. Gene expression analysis of independent murine and human RNA sequencing datasets point to a shared cDC1 lysosomal stress response state across various tumors. Modeling primary cDC1 behavior in lung tumors in vivo and ex vivo, we show that two distinct yet interconnected pathways converge to cause apoptosis of cDC1: mTOR inhibition leads to an increase in the proteolytic activity of lysosomes, while lysosomal membrane permeabilization (LMP) allows the release of proteolytic enzymes to the cytosol and apoptotic death. Pathway and regulon analysis of the cDC1 transcriptome suggest that mTOR inhibition and lysosomal stress happen downstream of type I IFNs. Accordingly, exposure of the Mutu cDC1 line to type I IFNs inhibits mTOR, stresses lysosomes and triggers LMP and death. Further supporting this finding, in mixed bone-marrow chimeras IFNRA deletion rescues primary cDC1s from mTOR inhibition, lysosomal stress, LMP and death. We have therefore elucidated IFN-induced lysosomal death as a key mechanism of cDC1s paucity in tumors that should be prevented to increase tumor immunity through reinvigoration of the cDC1 pool.

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Section: Discussionmentioning

confidence: 99%

Interferon-induced lysosomal membrane permeabilization and death cause cDC1-deserts in tumors

Aerakis

Chatzigeorgiou

Kerdidani

et al. 2022

Preprint

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“…The cDC2A subpopulation is involved in anti-inflammatory control, whereas the cDC2B subpopulation is found to produce TNFα and IL-6 [70]. Recently, some cDC2 subsets were also shown to cross-present Ag to CD8 + T cells [92,93] or further activate existing CD8 + T cells [94]. The human blood DC2 and DC3 subsets are shown to be potent stimulators of naïve T cell proliferation [71].…”

Section: Biology In Healthy Tissuementioning

confidence: 99%

Dendritic Cell-Based Immunotherapy in Multiple Myeloma: Challenges, Opportunities, and Future Directions

Verheye

Melgar

Deschoemaeker

et al. 2022

IJMS

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Immunotherapeutic approaches, including adoptive cell therapy, revolutionized treatment in multiple myeloma (MM). As dendritic cells (DCs) are professional antigen-presenting cells and key initiators of tumor-specific immune responses, DC-based immunotherapy represents an attractive therapeutic approach in cancer. The past years, various DC-based approaches, using particularly ex-vivo-generated monocyte-derived DCs, have been tested in preclinical and clinical MM studies. However, long-term and durable responses in MM patients were limited, potentially attributed to the source of monocyte-derived DCs and the immunosuppressive bone marrow microenvironment. In this review, we briefly summarize the DC development in the bone marrow niche and the phenotypical and functional characteristics of the major DC subsets. We address the known DC deficiencies in MM and give an overview of the DC-based vaccination protocols that were tested in MM patients. Lastly, we also provide strategies to improve the efficacy of DC vaccines using new, improved DC-based approaches and combination therapies for MM patients.

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“…obs.). A recent study on tumor‐associated cDC showed that type I IFN promotes MHC class I cross‐dressing of cDC2 155 . Comingling of cDC2 and cDC1 in splenic T zones after type I IFN exposure may enable cross‐dressing and enhanced CD8 T cell responses.…”

Section: Migrating To the T Zone To Sound The Alarmmentioning

confidence: 99%

Chemo‐ and mechanosensing by dendritic cells facilitate antigen surveillance in the spleen*

Liu

Duan

Cyster

2022

Immunological Reviews

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Spleen dendritic cells (DC) are critical for initiation of adaptive immune responses against blood‐borne invaders. Key to DC function is their positioning at sites of pathogen entry, and their abilities to selectively capture foreign antigens and promptly engage T cells. Focusing on conventional DC2 (cDC2), we discuss the contribution of chemoattractant receptors (EBI2 or GPR183, S1PR1, and CCR7) and integrins to cDC2 positioning and function. We give particular attention to a newly identified role in cDC2 for adhesion G‐protein coupled receptor E5 (Adgre5 or CD97) and its ligand CD55, detailing how this mechanosensing system contributes to splenic cDC2 positioning and homeostasis. Additional roles of CD97 in the immune system are reviewed. The ability of cDC2 to be activated by circulating missing self‐CD47 cells and to integrate multiple red blood cell (RBC)‐derived inputs is discussed. Finally, we describe the process of activated cDC2 migration to engage and prime helper T cells. Throughout the review, we consider the insights into cDC function in the spleen that have emerged from imaging studies.

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Type I interferon activates MHC class I-dressed CD11b+ conventional dendritic cells to promote protective anti-tumor CD8+ T cell immunity

Cited by 172 publications

References 95 publications

Interferon-induced lysosomal membrane permeabilization and death cause cDC1-deserts in tumors

Interferon-induced lysosomal membrane permeabilization and death cause cDC1-deserts in tumors

Dendritic Cell-Based Immunotherapy in Multiple Myeloma: Challenges, Opportunities, and Future Directions

Chemo‐ and mechanosensing by dendritic cells facilitate antigen surveillance in the spleen*

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